U.S. patent application number 15/662239 was filed with the patent office on 2018-09-13 for block co-poly(metal organic nanostructures) (bcpmons) and uses thereof.
The applicant listed for this patent is Massachusetts Institute of Technology. Invention is credited to Jeremiah A. Johnson, Michelle MacLeod, Yufeng Wang.
Application Number | 20180258233 15/662239 |
Document ID | / |
Family ID | 59684037 |
Filed Date | 2018-09-13 |
United States Patent
Application |
20180258233 |
Kind Code |
A9 |
Johnson; Jeremiah A. ; et
al. |
September 13, 2018 |
BLOCK CO-POLY(METAL ORGANIC NANOSTRUCTURES) (BCPMONS) AND USES
THEREOF
Abstract
The present disclosure provides (block co-polymer)-(metal
organic framework) conjugates (BCPMOFs), such as (block
co-polymer)-(metal organic nanostructure) conjugates (BCPMONs), and
thermoplastic elastomers, gels, and compositions thereof. Exemplary
BCPMONs include (block co-polymer)-(metal organic cage) conjugates
(BCPMOCs), (block co-polymer)-(metal organic paddlewheel)
conjugates, and (block co-polymer)-(metal organic square)
conjugates, such as BCPMONs of Formula (A), (B), or (C). Also
described herein are macromonomers for preparing the BCPMONs;
thermoplastic elastomers, gels, and compositions involving the
BCPMONs; methods of preparing the BCPMONs, thermoplastic
elastomers, gels, and compositions; and methods of using the
BCPMONs, thermoplastic elastomers, gels, and compositions.
##STR00001##
Inventors: |
Johnson; Jeremiah A.;
(Boston, MA) ; Wang; Yufeng; (Hong Kong, CN)
; MacLeod; Michelle; (Cambridge, MA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Massachusetts Institute of Technology |
Cambridge |
MA |
US |
|
|
Prior
Publication: |
|
Document Identifier |
Publication Date |
|
US 20180030213 A1 |
February 1, 2018 |
|
|
Family ID: |
59684037 |
Appl. No.: |
15/662239 |
Filed: |
July 27, 2017 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
62367630 |
Jul 27, 2016 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
C07F 15/00 20130101;
C08G 83/001 20130101; C08G 83/008 20130101; A61K 47/32 20130101;
C08F 293/005 20130101; C07F 15/0066 20130101; C08J 3/075 20130101;
C07F 3/06 20130101 |
International
Class: |
C08J 3/075 20060101
C08J003/075; C08F 293/00 20060101 C08F293/00; A61K 47/32 20060101
A61K047/32 |
Goverment Interests
GOVERNMENT SUPPORT
[0002] This invention was made with Government support under Grant
Nos. CHE-1334703 and CHE-1351646 awarded by the National Science
Foundation. The Government has certain rights in the invention.
Claims
1. A (block co-polymer)-(metal organic nanostructure) conjugate
(BCPMON) comprising: (a) a metal organic nanostructure comprising:
(i) x instances of a transition metal ion, wherein x is an integer
between 2 and 60, inclusive; and (ii) 2x instances of a ligand of
Formula (A): ##STR00110## wherein: Ring A is a substituted or
unsubstituted phenyl ring or a substituted or unsubstituted, 5- or
6-membered, monocyclic heteroaryl ring; each of X.sup.A, X.sup.B,
X.sup.C, and X.sup.D is independently O, S, N, NR.sup.A1, C, or
CR.sup.A2; X.sup.E is a bond, N, or CR.sup.A2; each instance of
R.sup.A1 is independently hydrogen, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, or a nitrogen protecting group; each
instance of R.sup.A2 is independently hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.a, --N(R.sup.a).sub.2,
--SR.sup.a, --CN, --SCN, --C(.dbd.NR.sup.a)R.sup.a,
--C(.dbd.NR.sup.a)OR.sup.a, --C(.dbd.NR.sup.a)N(R.sup.a).sub.2,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; each
instance of R.sup.a is independently hydrogen, substituted or
unsubstituted acyl, substituted or unsubstituted alkyl, substituted
or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, a nitrogen protecting
group when attached to a nitrogen atom, an oxygen protecting group
when attached to an oxygen atom, or a sulfur protecting group when
attached to a sulfur atom, or two instances of R.sup.a are joined
to form a substituted or unsubstituted heterocyclic or substituted
or unsubstituted heteroaryl ring; each instance of R.sup.B is
independently halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; m is 0, 1,
2, 3, or 4, as valency permits; each instance of R.sup.C is
independently halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; n is 0, 1,
2, 3, or 4, as valency permits; Z.sup.A is a bond or a substituted
or unsubstituted C.sub.1-4 hydrocarbon chain, optionally wherein
one or more chain atoms are independently replaced with
--C(.dbd.O)--, --O--, --S--, --NR.sup.ZA--, --N.dbd., or .dbd.N--,
wherein each instance of R.sup.ZA is independently hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen
protecting group; and Z.sup.B is a bond or a substituted or
unsubstituted C.sub.1-4 hydrocarbon chain, optionally wherein one
or more chain atoms are independently replaced with --C(.dbd.O)--,
--O--, --S--, --NR.sup.ZB--, --N.dbd., or .dbd.N--, wherein each
instance of R.sup.ZB is independently hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;
wherein each instance of the transition metal ion and two instances
of the ligand of Formula (A) form through coordination bonds a
coordination complex; wherein each of the coordination bonds is
formed between an instance of the transition metal ion and the
nitrogen atom labeled with 1' or 1'' of an instance of the ligand
of Formula (A); and wherein the maximum outer dimension of the
metal organic nanostructure is between 1 nm and 100 nm, inclusive;
and (b) two or more instances of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E, wherein: each
instance of L is independently a bond or a substituted or
unsubstituted C.sub.1-4 hydrocarbon chain, optionally wherein one
or more chain atoms are independently replaced with --C(.dbd.O)--,
--O--, --S--, --NR.sup.L--, --N.dbd., or .dbd.N--, wherein each
instance of R.sup.L is independently hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; each
instance of R is independently a diradical of a first polymer,
wherein: the glass transition temperature (T.sub.g) of each
instance of the first polymer is not higher than 20.degree. C.; and
the number-average molecular weight (M.sub.n) of the first polymer
is between 1,000 g/mol and 1,000,000 g/mol, inclusive; each
instance of G is independently a diradical of a second polymer,
wherein: the T.sub.g of each instance of the second polymer is
higher than 20.degree. C.; and the M.sub.n of the second polymer is
between 300 g/mol and 100,000 g/mol, inclusive; each instance of p
is independently 0, 1, 2, or 3; each instance of q is independently
0, 1, 2, or 3, provided that at least one instance of p and q is 1,
2, or 3; each instance of u is independently 0, 1, 2, or 3; each
instance of v is independently 0, 1, 2, or 3; and each instance of
E is independently hydrogen, halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sup.a, --N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; wherein:
each instance of -L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E is
independently directly covalently attached to an instance of the
ligand of Formula (A); and each two instances of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E are independently
directly covalently attached to the same instance or two different
instances of the ligand of Formula (A).
2. (canceled)
3. The BCPMON of claim 1, wherein the x instances of the transition
metal ion and the 2x instances of the ligand of Formula (A) form
through the coordination bonds a substantially spherical structure
or a substantially paddlewheel structure.
4-10. (canceled)
11. A (block co-polymer)-(metal organic nanostructure) conjugate
(BCPMON) comprising: (a) a metal organic nanostructure comprising:
(i) a transition metal ion; and (ii) four instances of a ligand of
Formula (B): ##STR00111## wherein: Ring A is a substituted or
unsubstituted phenyl ring or a substituted or unsubstituted, 5- or
6-membered, monocyclic heteroaryl ring; each of X.sup.A, X.sup.B,
X.sup.C, and X.sup.D is independently O, S, N, NR.sup.A1, C, or
CR.sup.A2; X.sup.E is a bond, N, or CR.sup.A2; each instance of
R.sup.A1 is independently hydrogen, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, or a nitrogen protecting group; each
instance of R.sup.A2 is independently hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.a, --N(R.sup.a).sub.2,
--SR.sup.a, --CN, --SCN, --C(.dbd.NR.sup.a)R.sup.a,
--C(.dbd.NR.sup.a)OR.sup.a, --C(.dbd.NR.sup.a)N(R.sup.a).sub.2,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; each
instance of R.sup.a is independently hydrogen, substituted or
unsubstituted acyl, substituted or unsubstituted alkyl, substituted
or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, a nitrogen protecting
group when attached to a nitrogen atom, an oxygen protecting group
when attached to an oxygen atom, or a sulfur protecting group when
attached to a sulfur atom, or two instances of R.sup.a are joined
to form a substituted or unsubstituted heterocyclic or substituted
or unsubstituted heteroaryl ring; each instance of R.sup.B is
independently halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; m is 0, 1,
2, 3, or 4, as valency permits; Z.sup.A is a bond or a substituted
or unsubstituted C.sub.1-4 hydrocarbon chain, optionally wherein
one or more chain atoms are independently replaced with
--C(.dbd.O)--, --O--, --S--, --NR.sup.ZA--, --N.dbd., or .dbd.N--,
wherein each instance of R.sup.ZA is independently hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen
protecting group; and wherein the transition metal ion and the four
instances of the ligand of Formula (B) form through coordination
bonds a coordination complex; wherein each of the coordination
bonds is formed between the transition metal ion and the nitrogen
atom labeled with 1' of each instance of the ligand of Formula (B);
and wherein the maximum outer dimension of the metal organic
nanostructure is between about 1 nm and about 100 nm, inclusive;
and (b) two or more instances of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E, wherein: each
instance of L is independently a bond or a substituted or
unsubstituted C.sub.1-4 hydrocarbon chain, optionally wherein one
or more chain atoms are independently replaced with --C(.dbd.O)--,
--O--, --S--, --NR.sup.L--, --N.dbd., or .dbd.N--, wherein each
instance of R.sup.L is independently hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; each
instance of R is independently a diradical of a first polymer,
wherein: the glass transition temperature (T.sub.g) of each
instance of the first polymer is not higher than 20.degree. C.; and
the number-average molecular weight (M.sub.n) of the first polymer
is between 1,000 g/mol and 1,000,000 g/mol, inclusive; each
instance of G is independently a diradical of a second polymer,
wherein: the T.sub.g of each instance of the second polymer is
higher than 20.degree. C.; and the M.sub.n of the second polymer is
between 300 g/mol and 100,000 g/mol, inclusive; each instance of p
is independently 0, 1, 2, or 3; each instance of q is independently
0, 1, 2, or 3, provided that at least one instance of p and q is 1,
2, or 3; each instance of u is independently 0, 1, 2, or 3; each
instance of v is independently 0, 1, 2, or 3; and each instance of
E is independently hydrogen, halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sup.a, --N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; wherein:
each instance of -L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E is
independently directly covalently attached to an instance the
ligand of Formula (B); and each two instances of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E are independently
directly covalently attached to the same instance or two different
instances of the ligand of Formula (B).
12. (canceled)
13. The BCPMON of claim 11, wherein the transition metal ion and
the four instances of the ligand of Formula (B) form through the
coordination bonds a substantially square structure.
14. (canceled)
15. A (block co-polymer)-(metal organic nanostructure) conjugate
(BCPMON) comprising: (i) y instances of a transition metal ion,
wherein y is an integer between 1 and 1,000, inclusive; and (ii) z
instances of a ligand of Formula (C): ##STR00112## wherein: z is an
integer between 2 and 200, inclusive; s is an integer between 2 and
10, inclusive; each instance of R.sup.D is independently hydrogen,
halogen, substituted or unsubstituted C.sub.1-6 alkyl, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; each
instance of T is independently a bond or a substituted or
unsubstituted C.sub.1-50 hydrocarbon chain, optionally wherein one
or more chain atoms are independently replaced with --C(.dbd.O)--,
--O--, --S--, --NR.sup.T--, --N.dbd., or .dbd.N--, wherein each
instance of R.sup.T is independently hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; W is
substituted or unsubstituted, C.sub.1-200 alkylene, substituted or
unsubstituted, C.sub.2-200 alkenylene, substituted or
unsubstituted, C.sub.2-200 alkynylene, substituted or
unsubstituted, C.sub.2-200 heteroalkylene, substituted or
unsubstituted, C.sub.2-200 heteroalkenylene, or C.sub.2-200
heteroalkynylene, wherein: optionally one or more carbons in each
instance of the substituted or unsubstituted, C.sub.1-200 alkylene,
substituted or unsubstituted, C.sub.2-200 alkenylene, substituted
or unsubstituted, C.sub.2-200 alkynylene, substituted or
unsubstituted, C.sub.2-200 heteroalkylene, substituted or
unsubstituted, C.sub.2-200 heteroalkenylene, and C.sub.2-200
heteroalkynylene are independently replaced with substituted or
unsubstituted carbocyclylene, substituted or unsubstituted
heterocyclylene, substituted or unsubstituted arylene, or
substituted or unsubstituted heteroarylene; and optionally one or
more heteroatoms in each instance of the substituted or
unsubstituted, C.sub.2-200 heteroalkylene, substituted or
unsubstituted, C.sub.2-200 heteroalkenylene, and substituted or
unsubstituted, C.sub.2-200 heteroalkynylene are independently
replaced with substituted or unsubstituted carbocyclylene,
substituted or unsubstituted heterocyclylene, substituted or
unsubstituted arylene, or substituted or unsubstituted
heteroarylene; each instance of R is independently a diradical of a
first polymer, wherein: the glass transition temperature (T.sub.g)
of each instance of the first polymer is not higher than 20.degree.
C.; and the number-average molecular weight (M.sub.n) of the first
polymer is between 1,000 g/mol and 1,000,000 g/mol, inclusive; each
instance of G is independently a diradical of a second polymer,
wherein: the T.sub.g of each instance of the second polymer is
higher than 20.degree. C.; and the M.sub.n of the second polymer is
between 300 g/mol and 100,000 g/mol, inclusive; each instance of p
is independently 0, 1, 2, or 3; each instance of q is independently
0, 1, 2, or 3, provided that at least one instance of p and q is 1,
2, or 3; each instance of u is independently 0, 1, 2, or 3; each
instance of v is independently 0, 1, 2, or 3; and each instance of
E is independently hydrogen, halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sup.a, --N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; and each
instance of R.sup.a is independently hydrogen, substituted or
unsubstituted acyl, substituted or unsubstituted alkyl, substituted
or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, a nitrogen protecting
group when attached to a nitrogen atom, an oxygen protecting group
when attached to an oxygen atom, or a sulfur protecting group when
attached to a sulfur atom, or two instances of R.sup.a are joined
to form a substituted or unsubstituted heterocyclic or substituted
or unsubstituted heteroaryl ring; wherein each instance of the
transition metal ion and at least one instance of the ligand of
Formula (C) form through one or more coordination bonds a
coordination complex; and wherein each of the coordination bonds is
formed between an instance of the transition metal ion and an
instance of the oxygen atom labeled with "*".
16. The BCPMON of claim 15, wherein at least one instance of the
coordination complex is substantively of the MOF-5 framework as
shown in FIG. 43.
17-36. (canceled)
37. A macromonomer of Formula (L): ##STR00113## wherein: Ring A is
a substituted or unsubstituted phenyl ring or a substituted or
unsubstituted, 5- or 6-membered, monocyclic heteroaryl ring; each
of X.sup.A, X.sup.B, X.sup.C, and X.sup.D is independently O, S, N,
NR.sup.A1, C, or CR.sup.A2; X.sup.E is a bond, N, or CR.sup.A2;
each instance of R.sup.A1 is independently hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, or a nitrogen protecting group; each
instance of R.sup.A2 is independently hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.a, --N(R.sup.a).sub.2,
--SR.sup.a, --CN, --SCN, --C(.dbd.NR.sup.a)R.sup.a,
--C(.dbd.NR.sup.a)OR.sup.a, --C(.dbd.NR.sup.a)N(R.sup.a).sub.2,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; each
instance of R.sup.a is independently hydrogen, substituted or
unsubstituted acyl, substituted or unsubstituted alkyl, substituted
or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, a nitrogen protecting
group when attached to a nitrogen atom, an oxygen protecting group
when attached to an oxygen atom, or a sulfur protecting group when
attached to a sulfur atom, or two instances of R.sup.a are joined
to form a substituted or unsubstituted heterocyclic or substituted
or unsubstituted heteroaryl ring; each instance of R.sup.B is
independently halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; m is 0, 1,
2, 3, or 4, as valency permits; each instance of R.sup.C is
independently halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; n is 0, 1,
2, 3, or 4, as valency permits; Z.sup.A is a bond or a substituted
or unsubstituted C.sub.1-4 hydrocarbon chain, optionally wherein
one or more chain atoms are independently replaced with
--C(.dbd.O)--, --O--, --S--, --NR.sup.ZA--, --N.dbd., or .dbd.N--,
wherein each instance of R.sup.ZA is independently hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen
protecting group; Z.sup.B is a bond or a substituted or
unsubstituted C.sub.1-4 hydrocarbon chain, optionally wherein one
or more chain atoms are independently replaced with --C(.dbd.O)--,
--O--, --S--, --NR.sup.ZB--, --N.dbd., or .dbd.N--, wherein each
instance of R.sup.ZB is independently hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group; r is
1, 2, or 3; each instance of L is independently a bond or a
substituted or unsubstituted C.sub.1-4 hydrocarbon chain,
optionally wherein one or more chain atoms are independently
replaced with --C(.dbd.O)--, --O--, --S--, --NR.sup.L--, --N.dbd.,
or .dbd.N--, wherein each instance of R.sup.L is independently
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a
nitrogen protecting group; each instance of R is independently a
diradical of a first polymer, wherein: the glass transition
temperature (T.sub.g) of each instance of the first polymer is not
higher than 20.degree. C.; and the number-average molecular weight
(M.sub.n) of the first polymer is between 1,000 g/mol and 1,000,000
g/mol, inclusive; each instance of G is independently a diradical
of a second polymer, wherein: the T.sub.g of each instance of the
second polymer is higher than 20.degree. C.; and the M.sub.n of the
second polymer is between 300 g/mol and 100,000 g/mol, inclusive;
each instance of p is independently 0, 1, 2, or 3; each instance of
q is independently 0, 1, 2, or 3, provided that at least one
instance of p and q is 1, 2, or 3; each instance of u is
independently 0, 1, 2, or 3; each instance of v is independently 0,
1, 2, or 3; and each instance of E is independently hydrogen,
halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2.
38-69. (canceled)
70. A macromonomer of Formula (M): ##STR00114## wherein: Ring A is
a substituted or unsubstituted phenyl ring or a substituted or
unsubstituted, 5- or 6-membered, monocyclic heteroaryl ring; each
of X.sup.A, X.sup.B, X.sup.C, and X.sup.D is independently O, S, N,
NR.sup.A1, C, or CR.sup.A2; X.sup.E is a bond, N, or CR.sup.A2;
each instance of R.sup.A1 is independently hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, or a nitrogen protecting group; each
instance of R.sup.A2 is independently hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.a, --N(R.sup.a).sub.2,
--SR.sup.a, --CN, --SCN, --C(.dbd.NR.sup.a)R.sup.a,
--C(.dbd.NR.sup.a)OR.sup.a, --C(.dbd.NR.sup.a)N(R.sup.a).sub.2,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; each
instance of R.sup.a is independently hydrogen, substituted or
unsubstituted acyl, substituted or unsubstituted alkyl, substituted
or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, a nitrogen protecting
group when attached to a nitrogen atom, an oxygen protecting group
when attached to an oxygen atom, or a sulfur protecting group when
attached to a sulfur atom, or two instances of R.sup.a are joined
to form a substituted or unsubstituted heterocyclic or substituted
or unsubstituted heteroaryl ring; each instance of R.sup.B is
independently halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; m is 0, 1,
2, 3, or 4, as valency permits; Z.sup.A is a bond or a substituted
or unsubstituted C.sub.1-4 hydrocarbon chain, optionally wherein
one or more chain atoms are independently replaced with
--C(.dbd.O)--, --O--, --S--, --NR.sup.ZA--, --N.dbd., or .dbd.N--,
wherein each instance of R.sup.ZA is independently hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen
protecting group; r is 1, 2, or 3; each instance of L is
independently a bond or a substituted or unsubstituted C.sub.1-4
hydrocarbon chain, optionally wherein one or more chain atoms are
independently replaced with --C(.dbd.O)--, --O--, --S--,
--NR.sup.L--, --N.dbd., or .dbd.N--, wherein each instance of
R.sup.L is independently hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, or a nitrogen protecting group; each instance of R
is independently a diradical of a first polymer, wherein: the glass
transition temperature (T.sub.g) of each instance of the first
polymer is not higher than 20.degree. C.; and the number-average
molecular weight (M.sub.n) of the first polymer is between 1,000
g/mol and 1,000,000 g/mol, inclusive; each instance of G is
independently a diradical of a second polymer, wherein: the T.sub.g
of each instance of the second polymer is higher than 20.degree.
C.; and the M.sub.n of the second polymer is between 300 g/mol and
100,000 g/mol, inclusive; each instance of p is independently 0, 1,
2, or 3; each instance of q is independently 0, 1, 2, or 3,
provided that at least one instance of p and q is 1, 2, or 3; each
instance of u is independently 0, 1, 2, or 3; each instance of v is
independently 0, 1, 2, or 3; and each instance of E is
independently hydrogen, halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sup.a, --N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.aa, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2.
71-112. (canceled)
113. A thermoplastic elastomer comprising two or more instances of
a BCPMON of claim 1.
114. A gel comprising two or more instances of a BCPMON of claim
1.
115-125. (canceled)
126. A composition comprising a BCPMON of claim 1; and optionally
an excipient.
127-143. (canceled)
144. A method of delivering an agent to a subject, the method
comprising administering to the subject a composition of claim
126.
145. (canceled)
146. A method of delivering an agent to a cell, the method
comprising contacting the cell with a composition of claim 126.
147. (canceled)
148. A kit comprising: a BCPMON of claim 1; and instructions for
using the BCPMON.
149. A method of preparing a BCPMON of claim 1 comprising
complexing a macromonomer of claim 37 with a transition metal
salt.
150. A method of preparing a thermoplastic elastomer of claim 113
comprising annealing two or more instances of a BCPMON of claim
1.
151. A method of preparing a gel of claim 114 comprising contacting
two or more instances of a BCPMON of claim 1 with a fluid.
152. (canceled)
153. A method of preparing a composition of claim 126 comprising
complexing a macromonomer of claim 37 with a transition metal salt
in the presence of an agent.
154-155. (canceled)
156. A thermoplastic elastomer prepared by a method of claim
150.
157. A gel prepared by a method of claim 151.
158-160. (canceled)
Description
RELATED APPLICATION
[0001] The present application claims priority under 35 U.S.C.
.sctn.119(e) to U.S. provisional application, U.S. Ser. No.
62/367,630, filed Jul. 27, 2016, which is incorporated herein by
reference.
BACKGROUND OF THE DISCLOSURE
[0003] Coordination-directed self-assembly of metal ions and
organic ligands is a powerful approach for the construction of two-
and three-dimensional molecular architectures..sup.1-10 Examples of
such structures range from discrete metal organic cycles and metal
organic cages/polyhedra (MOCs/MOPs).sup.11-27 to infinite metal
organic frameworks (MOFs).sup.28-31. By rational design of the
ligands and proper choice of the metal ions, these materials can
feature well-defined sizes, shapes, geometries, and porosity, which
enable applications in selective encapsulation, catalysis, sensing,
etc..sup.32-40
[0004] Inspired by the structural versatility as well as the
dynamic nature of metal coordination, much effort has recently been
devoted to the introduction of metal organic structures, which are
generally rigid, into elastic polymer networks. The goal is to
synthesize a new class of hybrid materials that have tunable
viscoelastic properties and are capable of realizing multiple
functions originally only possible for MOFs and MOCs..sup.41-46 For
example, in 2015 the synthesis of polyethylene glycol (PEG)
hydrogels crosslinked via metallosupramolecular assembly of
M.sub.xL.sub.y clusters (x metal ions and y ligands for each
junction; M.sub.4L.sub.4 squares were targeted).sup.47 derived from
bispyridyl tetrazine ligands bound to the ends of PEG chains and
either Fe.sup.2+ or Ni.sup.2+ ions was reported on..sup.48 These
gels were used as scaffolds for controlled photo-induced drug
release and enzymatic reactions. In the same year, Nitschke and
co-workers synthesized PEG hydrogels by crosslinking PEG chains
with M.sub.4L.sub.6 pyramidal MOC junctions..sup.49 Small
molecules--benzene and furan--could be encapsulated and released
from the MOCs in these materials. In 2016, Yang and co-workers
reported a post-assembly polymerization strategy to combine
thermo-responsive polymers with small metallacyles to yield
hydrogels with self-healing properties..sup.50 Later, Kitagawa and
co-workers reported the synthesis of coordination star polymers
containing copper-based MOCs using both divergent and convergent
methods..sup.51
[0005] Recently, the assembly of polymeric organogels connected
with MOC junctions was described..sup.52 These `polyMOC` gels
featured large cages, for instance, the M.sub.12L.sub.24 spherical
`Fujita cages`, which served as crosslink junctions between linear
polymer chains. Because the polymers used had ligands on both of
their ends, the resulting network was assembled in one step, which
produced polyMOCs with a high percentage of topological defects
such as primary loops. However, the use of large cage junctions
enabled the network to withstand those defects and at the same time
allowed for the introduction of additional functionality via
exchange of elastically inactive loops with functional free
ligands.
SUMMARY OF THE DISCLOSURE
[0006] The merger of metal organic frameworks (MOFs), such as metal
organic nanostructures (MONs) (e.g., metal organic cages (MOCs) and
metal organic squares (MOSs)), was envisioned with a classic
paradigm in polymer science: di-block copolymer (BCP)
self-assembly..sup.53-55 BCP assembly is a widely employed
"bottom-up" method for the fabrication of materials with periodic
structures on the order of .about.10 to 100 nm. Since MONs are
generally an order of magnitude smaller than this size range, it
was reasoned that hybrid materials based on MON assembly and BCP
assembly could feature unique hierarchical structures with
properties defined by order across various length scales. Such
structural hierarchy is common in biomaterials, but is often more
difficult to achieve in synthetic polymers.
[0007] Described herein are (block co-polymer)-(MON) conjugates
(BCPMONs), and thermoplastic elastomers, gels, and compositions
thereof. Also described herein are methods of preparing the
BCPMONs, thermoplastic elastomers, gels, and compositions. In
certain embodiments, the methods of preparing involve
macromonomers. Also described herein are the macromonomers. Further
described herein are methods of using the BCPMONs, thermoplastic
elastomers, gels, and compositions, and uses of the BCPMONs,
thermoplastic elastomers, gels, and compositions.
[0008] Certain MONs, and gels, compositions, methods, and uses
thereof, are described in U.S. patent application publication, US
2015/0225438, which is incorporated by reference.
[0009] In certain embodiments, the BCPMONs are (block
co-polymer)-(MOS) conjugates (BCPMOSs). In certain embodiments, the
BCPMONs are (block co-polymer)-(MOC) conjugates (BCPMOCs). In
certain embodiments, the BCPMONs are a class of materials derived
from stepwise MON assembly and BCP phase separation. The BCPMONs
may be constructed from BCPs that feature one glassy block, one
rubbery block, and a pyridyl ligand on the end of the rubbery block
(FIG. 1A). These BCPs undergo metal-coordination driven assembly in
solution to yield star polymers with well-defined .about.1 to 4 nm
MON cores and a precise number of polymer arms. When the solvent is
removed, or a solvent that is selective for one block of the BCP is
added, these materials may undergo phase separation and physical
crosslinking by forming glassy polymer domains to yield BCPMONs as
thermoplastic elastomers (TPE) or thermo-responsive organogels. The
synthesis of BCPMONs with large (.about.3.5 nm) Fujita-sphere
M.sub.12L.sub.24 MONs and small (.about.1.5 nm) paddlewheel
M.sub.2L.sub.4 MONs was demonstrated. Since the conformations of
attached BCP chains are restricted differently depending on the
MON, BCPMONs derived from these two MONs have different microphase
separated structures; e.g., MON assembly at short length scales
impacts BCP assembly at longer length scales. Furthermore, it was
shown that the structures and mechanical properties of BCPMONs may
be highly tunable and directly related to the MON and the BCP.
[0010] This work represents the first example wherein MON assembly
is merged with BCP phase separation to generate crosslinked
materials. The versatility of MON assembly and the rich diversity
of potential BCP structures provide great opportunities to develop
novel BCPMONs with a range of properties. For example, herein it is
shown that BCPs with a thermo-sensitive block can be employed to
fabricate thermo-responsive BCPMON organogels. The described
BCPMONs may also be useful for delivering an agent to a subject or
cell, for treating a disease in a subject, for preventing a disease
in a subject, or for enzymatic reactions.
[0011] In one aspect, the present disclosure provides (block
co-polymer)-(metal organic nanostructure) conjugates (BCPMONs)
comprising:
[0012] (a) a metal organic nanostructure comprising: [0013] (i) x
instances of a transition metal ion; and [0014] (ii) 2x instances
of a ligand of Formula (A):
##STR00002##
[0015] wherein each instance of the transition metal ion and two
instances of the ligand of Formula (A) form through coordination
bonds a coordination complex;
[0016] wherein each of the coordination bonds is formed between an
instance of the transition metal ion and the nitrogen atom labeled
with 1' or 1'' of an instance of the ligand of Formula (A); and
[0017] wherein the maximum outer dimension of the metal organic
nanostructure is between 1 nm and 100 nm, inclusive; and
[0018] (b) two or more instances of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E;
wherein:
[0019] each instance of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E is independently
directly covalently attached to an instance of the ligand of
Formula (A);
[0020] each two instances of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E are independently
directly covalently attached to the same instance or two different
instances of the ligand of Formula (A); and
[0021] the variables recited in this sentence are as described
herein.
[0022] In another aspect, the present disclosure provides BCPMONs
comprising:
[0023] (a) a metal organic nanostructure comprising: [0024] (i) a
transition metal ion; and [0025] (ii) four instances of a ligand of
Formula (B):
[0025] ##STR00003## [0026] wherein the transition metal ion and the
four instances of the ligand of Formula (B) form through
coordination bonds a coordination complex; [0027] wherein each of
the coordination bonds is formed between the transition metal ion
and the nitrogen atom labeled with 1' of each instance of the
ligand of Formula (B); and [0028] wherein the maximum outer
dimension of the metal organic nanostructure is between about 1 nm
and about 100 nm, inclusive; and
[0029] (b) two or more instances of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E,
wherein:
[0030] each instance of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E is independently
directly covalently attached to an instance the ligand of Formula
(B);
[0031] each two instances of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E are independently
directly covalently attached to the same instance or two different
instances of the ligand of Formula (B); and
[0032] the variables recited in this sentence are as described
herein.
[0033] Another aspect of the present disclosure relates to
thermoplastic elastomers comprising two or more instances of a
BCPMON described herein.
[0034] Another aspect of the present disclosure relates to gels
comprising two or more instances of a BCPMON described herein, and
a fluid.
[0035] Another aspect of the present disclosure relates to
macromonomers of Formula (L):
##STR00004##
wherein the variables recited in this sentence are as described
herein.
[0036] Another aspect of the present disclosure relates to
macromonomers of Formula (M):
##STR00005##
wherein the variables recited in this sentence are as described
herein.
[0037] Also provided herein are (block co-polymer)-(metal organic
framework) conjugates (BCPMOFs). In certain embodiments, a BCPMOF
is a (block co-polymer)-(metal organic nanostructure) conjugate
(BCPMON) (where the maximum outer dimension of the metal organic
nanostructure (MON) of the BCPMON is not larger than 1 .mu.m). In
certain embodiments, the BCPMON is a assembly of polymer-polyMOF
hybrids. The BCPMON may be prepared through iterative exponential
growth and/or "click" chemistry. The BCPMON may comprise
crystalline polyMOF domains embedded in an amorphous polymer (e.g.,
polystyrene (PS)) matrix.
[0038] Another aspect of the present disclosure relates to
compositions comprising: a BCPMON, thermoplastic elastomer, gel, or
macromonomer described herein; and optionally an excipient.
[0039] Another aspect of the present disclosure relates to methods
of delivering an agent to a subject, the methods comprising
administering to the subject a composition described herein.
[0040] Another aspect of the present disclosure relates to methods
of delivering an agent to a cell, the methods comprising contacting
the cell with a composition described herein.
[0041] Another aspect of the present disclosure relates to kits
comprising: a macromonomer, BCPMON, thermoplastic elastomer, gel,
or composition described herein; and instructions for using the
macromonomer, BCPMON, thermoplastic elastomer, gel, or composition
described herein.
[0042] Another aspect of the present disclosure relates to methods
of preparing a BCPMON described herein comprising complexing a
macromonomer described herein with a transition metal salt.
[0043] Another aspect of the present disclosure relates to methods
of preparing a thermoplastic elastomer described herein comprising
annealing two or more instances of a BCPMON described herein.
[0044] Another aspect of the present disclosure relates to methods
of preparing a gel described herein comprising contacting two or
more instances of a BCPMON described herein with a fluid.
[0045] Another aspect of the present disclosure relates to methods
of preparing a composition described herein comprising complexing a
macromonomer described herein with a transition metal salt in the
presence of an agent.
[0046] Another aspect of the present disclosure relates to
thermoplastic elastomers prepared by a method described herein.
[0047] Another aspect of the present disclosure relates to gels
prepared by a method described herein.
[0048] The journal article MacLeod et al., Polymer Chemistry, 12
Jul. 2017 (DOI: 10.1039/C7PY00922D) may be related to the present
disclosure and is incorporated herein by reference.
[0049] The details of one or more embodiments of the disclosure are
set forth herein. Other features, objects, and advantages of the
disclosure will be apparent from the Detailed Description, the
Figures, the Examples, and the Claims.
Definitions
[0050] Definitions of specific functional groups and chemical terms
are described in more detail below. The chemical elements are
identified in accordance with the Periodic Table of the Elements,
CAS version, Handbook of Chemistry and Physics, 75.sup.th Ed.,
inside cover, and specific functional groups are generally defined
as described therein. Additionally, general principles of organic
chemistry, as well as specific functional moieties and reactivity,
are described in Thomas Sorrell, Organic Chemistry, University
Science Books, Sausalito, 1999; Smith and March, March's Advanced
Organic Chemistry, 5.sup.th Edition, John Wiley & Sons, Inc.,
New York, 2001; Larock, Comprehensive Organic Transformations, VCH
Publishers, Inc., New York, 1989; and Carruthers, Some Modern
Methods of Organic Synthesis, 3rd Edition, Cambridge University
Press, Cambridge, 1987.
[0051] Compounds (e.g., ligands, macromonomers, BCPMONs) described
herein can comprise one or more asymmetric centers, and thus can
exist in various isomeric forms, e.g., enantiomers and/or
diastereomers. For example, the compounds described herein can be
in the form of an individual enantiomer, diastereomer or geometric
isomer, or can be in the form of a mixture of stereoisomers,
including racemic mixtures and mixtures enriched in one or more
stereoisomer. Isomers can be isolated from mixtures by methods
known to those skilled in the art, including chiral high pressure
liquid chromatography (HPLC) and the formation and crystallization
of chiral salts; or preferred isomers can be prepared by asymmetric
syntheses. See, for example, Jacques et al., Enantiomers, Racemates
and Resolutions (Wiley Interscience, New York, 1981); Wilen et al.,
Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon
Compounds (McGraw-Hill, N Y, 1962); and Wilen, Tables of Resolving
Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of
Notre Dame Press, Notre Dame, Ind. 1972). The invention
additionally encompasses compounds described herein as individual
isomers substantially free of other isomers, and alternatively, as
mixtures of various isomers.
[0052] When a range of values is listed, it is intended to
encompass each value and sub-range within the range. For example
"C.sub.1-6" is intended to encompass, C.sub.1, C.sub.2, C.sub.3,
C.sub.4, C.sub.5, C.sub.6, C.sub.1-6, C.sub.1-5, C.sub.1-4,
C.sub.1-3, C.sub.1-2, C.sub.2-6, C.sub.2-5, C.sub.2-4, C.sub.2-3,
C.sub.3-6, C.sub.3-5, C.sub.3-4, C.sub.4-6, C.sub.4-5, and
C.sub.5-6.
[0053] The term "aliphatic" refers to alkyl, alkenyl, alkynyl, and
carbocyclic groups. Likewise, the term "heteroaliphatic" refers to
heteroalkyl, heteroalkenyl, heteroalkynyl, and heterocyclic
groups.
[0054] "Alkyl" refers to a radical of a straight-chain or branched
saturated hydrocarbon group. In some embodiments, an alkyl group
has 1 to 20 carbon atoms ("C.sub.1-20 alkyl"). In some embodiments,
an alkyl group has 1 to 10 carbon atoms ("C.sub.1-10 alkyl"). In
some embodiments, an alkyl group has 1 to 9 carbon atoms
("C.sub.1-9 alkyl"). In some embodiments, an alkyl group has 1 to 8
carbon atoms ("C.sub.1-8 alkyl"). In some embodiments, an alkyl
group has 1 to 7 carbon atoms ("C.sub.1-7 alkyl"). In some
embodiments, an alkyl group has 1 to 6 carbon atoms ("C.sub.1-6
alkyl"). In some embodiments, an alkyl group has 1 to 5 carbon
atoms ("C.sub.1-5 alkyl"). In some embodiments, an alkyl group has
1 to 4 carbon atoms ("C.sub.1-4 alkyl"). In some embodiments, an
alkyl group has 1 to 3 carbon atoms ("C.sub.1-3 alkyl"). In some
embodiments, an alkyl group has 1 to 2 carbon atoms ("C.sub.1-2
alkyl"). In some embodiments, an alkyl group has 1 carbon atom
("C.sub.1 alkyl"). In some embodiments, an alkyl group has 2 to 6
carbon atoms ("C.sub.2-6 alkyl"). Examples of C.sub.1-6 alkyl
groups include methyl (C.sub.1), ethyl (C.sub.2), n-propyl
(C.sub.3), isopropyl (C.sub.3), n-butyl (C.sub.4), tert-butyl
(C.sub.4), sec-butyl (C.sub.4), iso-butyl (C.sub.4), n-pentyl
(C.sub.5), 3-pentanyl (C.sub.5), amyl (C.sub.5), neopentyl
(C.sub.5), 3-methyl-2-butanyl (C.sub.5), tertiary amyl (C.sub.5),
and n-hexyl (C.sub.6). Additional examples of alkyl groups include
n-heptyl (C.sub.7), n-octyl (C.sub.8), and the like. Unless
otherwise specified, each instance of an alkyl group is
independently optionally substituted, i.e., unsubstituted (an
"unsubstituted alkyl") or substituted (a "substituted alkyl") with
one or more substituents. In certain embodiments, the alkyl group
is unsubstituted C.sub.1-10 alkyl (e.g., --CH.sub.3). In certain
embodiments, the alkyl group is substituted C.sub.1-10 alkyl.
[0055] The term "heteroalkyl" refers to an alkyl group, which
further includes at least one heteroatom (e.g., 1, 2, 3, or 4
heteroatoms) selected from oxygen, nitrogen, or sulfur within
(i.e., inserted between adjacent carbon atoms of) and/or placed at
one or more terminal position(s) of the parent chain. In certain
embodiments, a heteroalkyl group refers to a saturated group having
from 1 to 10 carbon atoms and 1 or more heteroatoms within the
parent chain ("heteroC.sub.1-10 alkyl" or "C.sub.1-10
heteroalkyl"). In some embodiments, a heteroalkyl group is a
saturated group having 1 to 9 carbon atoms and 1 or more
heteroatoms within the parent chain ("heteroC.sub.1-9 alkyl"). In
some embodiments, a heteroalkyl group is a saturated group having 1
to 8 carbon atoms and 1 or more heteroatoms within the parent chain
("heteroC.sub.1-8 alkyl"). In some embodiments, a heteroalkyl group
is a saturated group having 1 to 7 carbon atoms and 1 or more
heteroatoms within the parent chain ("heteroC.sub.1-7 alkyl"). In
some embodiments, a heteroalkyl group is a saturated group having 1
to 6 carbon atoms and 1 or more heteroatoms within the parent chain
("heteroC.sub.1-6 alkyl"). In some embodiments, a heteroalkyl group
is a saturated group having 1 to 5 carbon atoms and 1 or 2
heteroatoms within the parent chain ("heteroC.sub.1-5 alkyl"). In
some embodiments, a heteroalkyl group is a saturated group having 1
to 4 carbon atoms and 1 or 2 heteroatoms within the parent chain
("heteroC.sub.1-4 alkyl"). In some embodiments, a heteroalkyl group
is a saturated group having 1 to 3 carbon atoms and 1 heteroatom
within the parent chain ("heteroC.sub.1-3 alkyl"). In some
embodiments, a heteroalkyl group is a saturated group having 1 to 2
carbon atoms and 1 heteroatom within the parent chain
("heteroC.sub.1-2 alkyl"). In some embodiments, a heteroalkyl group
is a saturated group having 1 carbon atom and 1 heteroatom
("heteroC.sub.1 alkyl"). In some embodiments, a heteroalkyl group
is a saturated group having 2 to 6 carbon atoms and 1 or 2
heteroatoms within the parent chain ("heteroC.sub.2-6 alkyl").
Unless otherwise specified, each instance of a heteroalkyl group is
independently unsubstituted (an "unsubstituted heteroalkyl") or
substituted (a "substituted heteroalkyl") with one or more
substituents. In certain embodiments, the heteroalkyl group is an
unsubstituted heteroC.sub.1-10 alkyl. In certain embodiments, the
heteroalkyl group is a substituted heteroC.sub.1-10 alkyl.
[0056] "Alkenyl" refers to a radical of a straight-chain or
branched hydrocarbon group having one or more carbon-carbon double
bonds and no triple bonds. In some embodiments, an alkenyl group
has 2 to 20 carbon atoms ("C.sub.2-20 alkenyl"). In some
embodiments, an alkenyl group has 2 to 10 carbon atoms ("C.sub.2-10
alkenyl"). In some embodiments, an alkenyl group has 2 to 9 carbon
atoms ("C.sub.2-9 alkenyl"). In some embodiments, an alkenyl group
has 2 to 8 carbon atoms ("C.sub.2-8 alkenyl"). In some embodiments,
an alkenyl group has 2 to 7 carbon atoms ("C.sub.2-7 alkenyl"). In
some embodiments, an alkenyl group has 2 to 6 carbon atoms
("C.sub.2-6 alkenyl"). In some embodiments, an alkenyl group has 2
to 5 carbon atoms ("C.sub.2-5 alkenyl"). In some embodiments, an
alkenyl group has 2 to 4 carbon atoms ("C.sub.2-4 alkenyl"). In
some embodiments, an alkenyl group has 2 to 3 carbon atoms
("C.sub.2-3 alkenyl"). In some embodiments, an alkenyl group has 2
carbon atoms ("C.sub.2 alkenyl"). The one or more carbon-carbon
double bonds can be internal (such as in 2-butenyl) or terminal
(such as in 1-butenyl). Examples of C.sub.2-4 alkenyl groups
include ethenyl (C.sub.2), 1-propenyl (C.sub.3), 2-propenyl
(C.sub.3), 1-butenyl (C.sub.4), 2-butenyl (C.sub.4), butadienyl
(C.sub.4), and the like. Examples of C.sub.2-6 alkenyl groups
include the aforementioned C.sub.2-4 alkenyl groups as well as
pentenyl (C.sub.5), pentadienyl (C.sub.5), hexenyl (C.sub.6), and
the like. Additional examples of alkenyl include heptenyl
(C.sub.7), octenyl (C.sub.8), octatrienyl (C.sub.8), and the like.
Unless otherwise specified, each instance of an alkenyl group is
independently optionally substituted, i.e., unsubstituted (an
"unsubstituted alkenyl") or substituted (a "substituted alkenyl")
with one or more substituents. In certain embodiments, the alkenyl
group is unsubstituted C.sub.2-10 alkenyl. In certain embodiments,
the alkenyl group is substituted C.sub.2-10 alkenyl. In an alkenyl
group, a C.dbd.C double bond for which the stereochemistry is
unspecified (e.g., --CH.dbd.CHCH.sub.3 or
##STR00006##
may be an (E)- or (Z)-double bond.
[0057] The term "heteroalkenyl" refers to an alkenyl group, which
further includes at least one heteroatom (e.g., 1, 2, 3, or 4
heteroatoms) selected from oxygen, nitrogen, or sulfur within
(i.e., inserted between adjacent carbon atoms of) and/or placed at
one or more terminal position(s) of the parent chain. In certain
embodiments, a heteroalkenyl group refers to a group having from 2
to 10 carbon atoms, at least one double bond, and 1 or more
heteroatoms within the parent chain ("heteroC.sub.2-10 alkenyl").
In some embodiments, a heteroalkenyl group has 2 to 9 carbon atoms
at least one double bond, and 1 or more heteroatoms within the
parent chain ("heteroC.sub.2-9 alkenyl"). In some embodiments, a
heteroalkenyl group has 2 to 8 carbon atoms, at least one double
bond, and 1 or more heteroatoms within the parent chain
("heteroC.sub.2-8 alkenyl"). In some embodiments, a heteroalkenyl
group has 2 to 7 carbon atoms, at least one double bond, and 1 or
more heteroatoms within the parent chain ("heteroC.sub.2-7
alkenyl"). In some embodiments, a heteroalkenyl group has 2 to 6
carbon atoms, at least one double bond, and 1 or more heteroatoms
within the parent chain ("heteroC.sub.2-6 alkenyl"). In some
embodiments, a heteroalkenyl group has 2 to 5 carbon atoms, at
least one double bond, and 1 or 2 heteroatoms within the parent
chain ("heteroC.sub.2-5 alkenyl"). In some embodiments, a
heteroalkenyl group has 2 to 4 carbon atoms, at least one double
bond, and 1 or 2 heteroatoms within the parent chain
("heteroC.sub.2-4 alkenyl"). In some embodiments, a heteroalkenyl
group has 2 to 3 carbon atoms, at least one double bond, and 1
heteroatom within the parent chain ("heteroC.sub.2-3 alkenyl"). In
some embodiments, a heteroalkenyl group has 2 to 6 carbon atoms, at
least one double bond, and 1 or 2 heteroatoms within the parent
chain ("heteroC.sub.2-6alkenyl"). Unless otherwise specified, each
instance of a heteroalkenyl group is independently unsubstituted
(an "unsubstituted heteroalkenyl") or substituted (a "substituted
heteroalkenyl") with one or more substituents. In certain
embodiments, the heteroalkenyl group is an unsubstituted
heteroC.sub.2-10 alkenyl. In certain embodiments, the heteroalkenyl
group is a substituted heteroC.sub.2-10 alkenyl.
[0058] "Alkynyl" refers to a radical of a straight-chain or
branched hydrocarbon group having one or more carbon-carbon triple
bonds and optionally one or more double bonds. In some embodiments,
an alkynyl group has 2 to 20 carbon atoms ("C.sub.2-20 alkynyl").
In some embodiments, an alkynyl group has 2 to 10 carbon atoms
("C.sub.2-10 alkynyl"). In some embodiments, an alkynyl group has 2
to 9 carbon atoms ("C.sub.2-9 alkynyl"). In some embodiments, an
alkynyl group has 2 to 8 carbon atoms ("C.sub.2-8 alkynyl"). In
some embodiments, an alkynyl group has 2 to 7 carbon atoms
("C.sub.2-7 alkynyl"). In some embodiments, an alkynyl group has 2
to 6 carbon atoms ("C.sub.2-6 alkynyl"). In some embodiments, an
alkynyl group has 2 to 5 carbon atoms ("C.sub.2-5 alkynyl"). In
some embodiments, an alkynyl group has 2 to 4 carbon atoms
("C.sub.2-4 alkynyl"). In some embodiments, an alkynyl group has 2
to 3 carbon atoms ("C.sub.2-3 alkynyl"). In some embodiments, an
alkynyl group has 2 carbon atoms ("C.sub.2 alkynyl"). The one or
more carbon-carbon triple bonds can be internal (such as in
2-butynyl) or terminal (such as in 1-butynyl). Examples of
C.sub.2-4 alkynyl groups include, without limitation, ethynyl
(C.sub.2), 1-propynyl (C.sub.3), 2-propynyl (C.sub.3), 1-butynyl
(C.sub.4), 2-butynyl (C.sub.4), and the like. Examples of C.sub.2-6
alkenyl groups include the aforementioned C.sub.2-4 alkynyl groups
as well as pentynyl (C.sub.5), hexynyl (C.sub.6), and the like.
Additional examples of alkynyl include heptynyl (C.sub.7), octynyl
(C.sub.8), and the like. Unless otherwise specified, each instance
of an alkynyl group is independently optionally substituted, i.e.,
unsubstituted (an "unsubstituted alkynyl") or substituted (a
"substituted alkynyl") with one or more substituents. In certain
embodiments, the alkynyl group is unsubstituted C.sub.2-10 alkynyl.
In certain embodiments, the alkynyl group is substituted C.sub.2-10
alkynyl.
[0059] The term "heteroalkynyl" refers to an alkynyl group, which
further includes at least one heteroatom (e.g., 1, 2, 3, or 4
heteroatoms) selected from oxygen, nitrogen, or sulfur within
(i.e., inserted between adjacent carbon atoms of) and/or placed at
one or more terminal position(s) of the parent chain. In certain
embodiments, a heteroalkynyl group refers to a group having from 2
to 10 carbon atoms, at least one triple bond, and 1 or more
heteroatoms within the parent chain ("heteroC.sub.2-10 alkynyl").
In some embodiments, a heteroalkynyl group has 2 to 9 carbon atoms,
at least one triple bond, and 1 or more heteroatoms within the
parent chain ("heteroC.sub.2-9 alkynyl"). In some embodiments, a
heteroalkynyl group has 2 to 8 carbon atoms, at least one triple
bond, and 1 or more heteroatoms within the parent chain
("heteroC.sub.2-8 alkynyl"). In some embodiments, a heteroalkynyl
group has 2 to 7 carbon atoms, at least one triple bond, and 1 or
more heteroatoms within the parent chain ("heteroC.sub.2-7
alkynyl"). In some embodiments, a heteroalkynyl group has 2 to 6
carbon atoms, at least one triple bond, and 1 or more heteroatoms
within the parent chain ("heteroC.sub.2-6 alkynyl"). In some
embodiments, a heteroalkynyl group has 2 to 5 carbon atoms, at
least one triple bond, and 1 or 2 heteroatoms within the parent
chain ("heteroC.sub.2-5 alkynyl"). In some embodiments, a
heteroalkynyl group has 2 to 4 carbon atoms, at least one triple
bond, and 1 or 2 heteroatoms within the parent chain
("heteroC.sub.2-4 alkynyl"). In some embodiments, a heteroalkynyl
group has 2 to 3 carbon atoms, at least one triple bond, and 1
heteroatom within the parent chain ("heteroC.sub.2-3 alkynyl"). In
some embodiments, a heteroalkynyl group has 2 to 6 carbon atoms, at
least one triple bond, and 1 or 2 heteroatoms within the parent
chain ("heteroC.sub.2-6 alkynyl"). Unless otherwise specified, each
instance of a heteroalkynyl group is independently unsubstituted
(an "unsubstituted heteroalkynyl") or substituted (a "substituted
heteroalkynyl") with one or more substituents. In certain
embodiments, the heteroalkynyl group is an unsubstituted
heteroC.sub.2-10 alkynyl. In certain embodiments, the heteroalkynyl
group is a substituted heteroC.sub.2-10 alkynyl. The term
"heteroatom" refers to an atom that is not hydrogen or carbon. In
certain embodiments, the heteroatom is nitrogen. In certain
embodiments, the heteroatom is oxygen. In certain embodiments, the
heteroatom is sulfur.
[0060] The term "heteroatom" refers to an atom that is not hydrogen
or carbon. In certain embodiments, the heteroatom is nitrogen. In
certain embodiments, the heteroatom is oxygen. In certain
embodiments, the heteroatom is sulfur.
[0061] The term "carbocyclyl" or "carbocyclic" refers to a radical
of a non-aromatic cyclic hydrocarbon group having from 3 to 14 ring
carbon atoms ("C.sub.3-14 carbocyclyl") and zero heteroatoms in the
non-aromatic ring system. In some embodiments, a carbocyclyl group
has 3 to 10 ring carbon atoms ("C.sub.3-10 carbocyclyl"). In some
embodiments, a carbocyclyl group has 3 to 8 ring carbon atoms
("C.sub.3-8 carbocyclyl"). In some embodiments, a carbocyclyl group
has 3 to 7 ring carbon atoms ("C.sub.3-7 carbocyclyl"). In some
embodiments, a carbocyclyl group has 3 to 6 ring carbon atoms
("C.sub.3-6 carbocyclyl"). In some embodiments, a carbocyclyl group
has 4 to 6 ring carbon atoms ("C.sub.4-6 carbocyclyl"). In some
embodiments, a carbocyclyl group has 5 to 6 ring carbon atoms
("C.sub.5-6 carbocyclyl"). In some embodiments, a carbocyclyl group
has 5 to 10 ring carbon atoms ("C.sub.5-10 carbocyclyl"). Exemplary
C.sub.3-6 carbocyclyl groups include, without limitation,
cyclopropyl (C.sub.3), cyclopropenyl (C.sub.3), cyclobutyl
(C.sub.4), cyclobutenyl (C.sub.4), cyclopentyl (C.sub.5),
cyclopentenyl (C.sub.5), cyclohexyl (C.sub.6), cyclohexenyl
(C.sub.6), cyclohexadienyl (C.sub.6), and the like. Exemplary
C.sub.3-8 carbocyclyl groups include, without limitation, the
aforementioned C.sub.3-6 carbocyclyl groups as well as cycloheptyl
(C.sub.7), cycloheptenyl (C.sub.7), cycloheptadienyl (C.sub.7),
cycloheptatrienyl (C.sub.7), cyclooctyl (C.sub.8), cyclooctenyl
(C.sub.8), bicyclo[2.2.1]heptanyl (C.sub.7), bicyclo[2.2.2]octanyl
(C.sub.8), and the like. Exemplary C.sub.3-10 carbocyclyl groups
include, without limitation, the aforementioned C.sub.3-8
carbocyclyl groups as well as cyclononyl (C.sub.9), cyclononenyl
(C.sub.9), cyclodecyl (C.sub.10), cyclodecenyl (C.sub.10),
octahydro-1H-indenyl (C.sub.9), decahydronaphthalenyl (C.sub.10),
spiro[4.5]decanyl (C.sub.10), and the like. As the foregoing
examples illustrate, in certain embodiments, the carbocyclyl group
is either monocyclic ("monocyclic carbocyclyl") or polycyclic
(e.g., containing a fused, bridged or spiro ring system such as a
bicyclic system ("bicyclic carbocyclyl") or tricyclic system
("tricyclic carbocyclyl")) and can be saturated or can contain one
or more carbon-carbon double or triple bonds. "Carbocyclyl" also
includes ring systems wherein the carbocyclyl ring, as defined
above, is fused with one or more aryl or heteroaryl groups wherein
the point of attachment is on the carbocyclyl ring, and in such
instances, the number of carbons continue to designate the number
of carbons in the carbocyclic ring system. Unless otherwise
specified, each instance of a carbocyclyl group is independently
unsubstituted (an "unsubstituted carbocyclyl") or substituted (a
"substituted carbocyclyl") with one or more substituents. In
certain embodiments, the carbocyclyl group is an unsubstituted
C.sub.3-14 carbocyclyl. In certain embodiments, the carbocyclyl
group is a substituted C.sub.3-14 carbocyclyl.
[0062] In some embodiments, "carbocyclyl" is a monocyclic,
saturated carbocyclyl group having from 3 to 14 ring carbon atoms
("C.sub.3-14 cycloalkyl"). In some embodiments, a cycloalkyl group
has 3 to 10 ring carbon atoms ("C.sub.3-10 cycloalkyl"). In some
embodiments, a cycloalkyl group has 3 to 8 ring carbon atoms
("C.sub.3-8 cycloalkyl"). In some embodiments, a cycloalkyl group
has 3 to 6 ring carbon atoms ("C.sub.3-6 cycloalkyl"). In some
embodiments, a cycloalkyl group has 4 to 6 ring carbon atoms
("C.sub.4-6 cycloalkyl"). In some embodiments, a cycloalkyl group
has 5 to 6 ring carbon atoms ("C.sub.5-6 cycloalkyl"). In some
embodiments, a cycloalkyl group has 5 to 10 ring carbon atoms
("C.sub.5-10 cycloalkyl"). Examples of C.sub.5-6 cycloalkyl groups
include cyclopentyl (C.sub.5) and cyclohexyl (C.sub.5). Examples of
C.sub.3-6 cycloalkyl groups include the aforementioned C.sub.5-6
cycloalkyl groups as well as cyclopropyl (C.sub.3) and cyclobutyl
(C.sub.4). Examples of C.sub.3-8 cycloalkyl groups include the
aforementioned C.sub.3-6 cycloalkyl groups as well as cycloheptyl
(C.sub.7) and cyclooctyl (C.sub.8). Unless otherwise specified,
each instance of a cycloalkyl group is independently unsubstituted
(an "unsubstituted cycloalkyl") or substituted (a "substituted
cycloalkyl") with one or more substituents. In certain embodiments,
the cycloalkyl group is an unsubstituted C.sub.3-14 cycloalkyl. In
certain embodiments, the cycloalkyl group is a substituted
C.sub.3-14 cycloalkyl.
[0063] "Heterocyclyl" or "heterocyclic" refers to a radical of a 3-
to 10-membered non-aromatic ring system having ring carbon atoms
and 1 to 4 ring heteroatoms, wherein each heteroatom is
independently selected from nitrogen, oxygen, sulfur, boron,
phosphorus, and silicon ("3-10 membered heterocyclyl"). In
heterocyclyl groups that contain one or more nitrogen atoms, the
point of attachment can be a carbon or nitrogen atom, as valency
permits. A heterocyclyl group can either be monocyclic ("monocyclic
heterocyclyl") or a fused, bridged or spiro ring system such as a
bicyclic system ("bicyclic heterocyclyl"), and can be saturated or
can be partially unsaturated. Heterocyclyl bicyclic ring systems
can include one or more heteroatoms in one or both rings.
"Heterocyclyl" also includes ring systems wherein the heterocyclic
ring, as defined above, is fused with one or more carbocyclyl
groups wherein the point of attachment is either on the carbocyclyl
or heterocyclic ring, or ring systems wherein the heterocyclic
ring, as defined above, is fused with one or more aryl or
heteroaryl groups, wherein the point of attachment is on the
heterocyclic ring, and in such instances, the number of ring
members continue to designate the number of ring members in the
heterocyclic ring system. Unless otherwise specified, each instance
of heterocyclyl is independently optionally substituted, i.e.,
unsubstituted (an "unsubstituted heterocyclyl") or substituted (a
"substituted heterocyclyl") with one or more substituents. In
certain embodiments, the heterocyclyl group is unsubstituted 3-10
membered heterocyclyl. In certain embodiments, the heterocyclyl
group is substituted 3-10 membered heterocyclyl.
[0064] In some embodiments, a heterocyclyl group is a 5-10 membered
non-aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms, wherein each heteroatom is independently selected from
nitrogen, oxygen, sulfur, boron, phosphorus, and silicon ("5-10
membered heterocyclyl"). In some embodiments, a heterocyclyl group
is a 5-8 membered non-aromatic ring system having ring carbon atoms
and 1-4 ring heteroatoms, wherein each heteroatom is independently
selected from nitrogen, oxygen, and sulfur ("5-8 membered
heterocyclyl"). In some embodiments, a heterocyclyl group is a 5-6
membered non-aromatic ring system having ring carbon atoms and 1-4
ring heteroatoms, wherein each heteroatom is independently selected
from nitrogen, oxygen, and sulfur ("5-6 membered heterocyclyl"). In
some embodiments, the 5-6 membered heterocyclyl has 1-3 ring
heteroatoms selected from nitrogen, oxygen, and sulfur. In some
embodiments, the 5-6 membered heterocyclyl has 1-2 ring heteroatoms
selected from nitrogen, oxygen, and sulfur. In some embodiments,
the 5-6 membered heterocyclyl has one ring heteroatom selected from
nitrogen, oxygen, and sulfur.
[0065] Exemplary 3-membered heterocyclyl groups containing one
heteroatom include, without limitation, azirdinyl, oxiranyl, and
thiiranyl. Exemplary 4-membered heterocyclyl groups containing one
heteroatom include, without limitation, azetidinyl, oxetanyl and
thietanyl. Exemplary 5-membered heterocyclyl groups containing one
heteroatom include, without limitation, tetrahydrofuranyl,
dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl,
pyrrolidinyl, dihydropyrrolyl, and pyrrolyl-2,5-dione. Exemplary
5-membered heterocyclyl groups containing two heteroatoms include,
without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and
oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups
containing three heteroatoms include, without limitation,
triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary
6-membered heterocyclyl groups containing one heteroatom include,
without limitation, piperidinyl, tetrahydropyranyl,
dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl
groups containing two heteroatoms include, without limitation,
piperazinyl, morpholinyl, dithianyl, and dioxanyl. Exemplary
6-membered heterocyclyl groups containing three heteroatoms
include, without limitation, triazinanyl. Exemplary 7-membered
heterocyclyl groups containing one heteroatom include, without
limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered
heterocyclyl groups containing one heteroatom include, without
limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 5-membered
heterocyclyl groups fused to a C.sub.6 aryl ring (also referred to
herein as a 5,6-bicyclic heterocyclic ring) include, without
limitation, indolinyl, isoindolinyl, dihydrobenzofuranyl,
dihydrobenzothienyl, benzoxazolinonyl, and the like. Exemplary
6-membered heterocyclyl groups fused to an aryl ring (also referred
to herein as a 6,6-bicyclic heterocyclic ring) include, without
limitation, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the
like.
[0066] "Aryl" refers to a radical of a monocyclic or polycyclic
(e.g., bicyclic or tricyclic) 4n+2 aromatic ring system (e.g.,
having 6, 10, or 14 p electrons shared in a cyclic array) having
6-14 ring carbon atoms and zero heteroatoms provided in the
aromatic ring system ("C.sub.6-14 aryl"). In some embodiments, an
aryl group has six ring carbon atoms ("C.sub.6 aryl"; e.g.,
phenyl). In some embodiments, an aryl group has ten ring carbon
atoms ("C.sub.10 aryl"; e.g., naphthyl such as 1-naphthyl and
2-naphthyl). In some embodiments, an aryl group has fourteen ring
carbon atoms ("C.sub.14 aryl"; e.g., anthracyl). "Aryl" also
includes ring systems wherein the aryl ring, as defined above, is
fused with one or more carbocyclyl or heterocyclyl groups wherein
the radical or point of attachment is on the aryl ring, and in such
instances, the number of carbon atoms continue to designate the
number of carbon atoms in the aryl ring system. Unless otherwise
specified, each instance of an aryl group is independently
optionally substituted, i.e., unsubstituted (an "unsubstituted
aryl") or substituted (a "substituted aryl") with one or more
substituents. In certain embodiments, the aryl group is
unsubstituted C.sub.6-14 aryl. In certain embodiments, the aryl
group is substituted C.sub.6-14 aryl.
[0067] "Aralkyl" is a subset of alkyl and aryl and refers to an
optionally substituted alkyl group substituted by an optionally
substituted aryl group. In certain embodiments, the aralkyl is
optionally substituted benzyl. In certain embodiments, the aralkyl
is benzyl. In certain embodiments, the aralkyl is optionally
substituted phenethyl. In certain embodiments, the aralkyl is
phenethyl.
[0068] "Heteroaryl" refers to a radical of a 5-10 membered
monocyclic or bicyclic 4n+2 aromatic ring system (e.g., having 6 or
10 p electrons shared in a cyclic array) having ring carbon atoms
and 1-4 ring heteroatoms provided in the aromatic ring system,
wherein each heteroatom is independently selected from nitrogen,
oxygen and sulfur ("5-10 membered heteroaryl"). In heteroaryl
groups that contain one or more nitrogen atoms, the point of
attachment can be a carbon or nitrogen atom, as valency permits.
Heteroaryl bicyclic ring systems can include one or more
heteroatoms in one or both rings. "Heteroaryl" includes ring
systems wherein the heteroaryl ring, as defined above, is fused
with one or more carbocyclyl or heterocyclyl groups wherein the
point of attachment is on the heteroaryl ring, and in such
instances, the number of ring members continue to designate the
number of ring members in the heteroaryl ring system. "Heteroaryl"
also includes ring systems wherein the heteroaryl ring, as defined
above, is fused with one or more aryl groups wherein the point of
attachment is either on the aryl or heteroaryl ring, and in such
instances, the number of ring members designates the number of ring
members in the fused (aryl/heteroaryl) ring system. Bicyclic
heteroaryl groups wherein one ring does not contain a heteroatom
(e.g., indolyl, quinolinyl, carbazolyl, and the like) the point of
attachment can be on either ring, i.e., either the ring bearing a
heteroatom (e.g., 2-indolyl) or the ring that does not contain a
heteroatom (e.g., 5-indolyl).
[0069] In some embodiments, a heteroaryl group is a 5-10 membered
aromatic ring system having ring carbon atoms and 1-4 ring
heteroatoms provided in the aromatic ring system, wherein each
heteroatom is independently selected from nitrogen, oxygen, and
sulfur ("5-10 membered heteroaryl"). In some embodiments, a
heteroaryl group is a 5-8 membered aromatic ring system having ring
carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring
system, wherein each heteroatom is independently selected from
nitrogen, oxygen, and sulfur ("5-8 membered heteroaryl"). In some
embodiments, a heteroaryl group is a 5-6 membered aromatic ring
system having ring carbon atoms and 1-4 ring heteroatoms provided
in the aromatic ring system, wherein each heteroatom is
independently selected from nitrogen, oxygen, and sulfur ("5-6
membered heteroaryl"). In some embodiments, the 5-6 membered
heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen,
and sulfur. In some embodiments, the 5-6 membered heteroaryl has
1-2 ring heteroatoms selected from nitrogen, oxygen, and sulfur. In
some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom
selected from nitrogen, oxygen, and sulfur. Unless otherwise
specified, each instance of a heteroaryl group is independently
optionally substituted, i.e., unsubstituted (an "unsubstituted
heteroaryl") or substituted (a "substituted heteroaryl") with one
or more substituents. In certain embodiments, the heteroaryl group
is unsubstituted 5-14 membered heteroaryl. In certain embodiments,
the heteroaryl group is substituted 5-14 membered heteroaryl.
[0070] Exemplary 5-membered heteroaryl groups containing one
heteroatom include, without limitation, pyrrolyl, furanyl, and
thiophenyl. Exemplary 5-membered heteroaryl groups containing two
heteroatoms include, without limitation, imidazolyl, pyrazolyl,
oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary
5-membered heteroaryl groups containing three heteroatoms include,
without limitation, triazolyl, oxadiazolyl, and thiadiazolyl.
Exemplary 5-membered heteroaryl groups containing four heteroatoms
include, without limitation, tetrazolyl. Exemplary 6-membered
heteroaryl groups containing one heteroatom include, without
limitation, pyridinyl. Exemplary 6-membered heteroaryl groups
containing two heteroatoms include, without limitation,
pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered
heteroaryl groups containing three or four heteroatoms include,
without limitation, triazinyl and tetrazinyl, respectively.
Exemplary 7-membered heteroaryl groups containing one heteroatom
include, without limitation, azepinyl, oxepinyl, and thiepinyl.
Exemplary 5,6-bicyclic heteroaryl groups include, without
limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl,
benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl,
benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl,
benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and
purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without
limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl,
cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.
[0071] "Heteroaralkyl" is a subset of alkyl and heteroaryl and
refers to an optionally substituted alkyl group substituted by an
optionally substituted heteroaryl group.
[0072] "Unsaturated" or "partially unsaturated" refers to a group
that includes at least one double or triple bond. A "partially
unsaturated" ring system is further intended to encompass rings
having multiple sites of unsaturation, but is not intended to
include aromatic groups (e.g., aryl or heteroaryl groups) as herein
defined. Likewise, "saturated" refers to a group that does not
contain a double or triple bond, i.e., contains all single
bonds.
[0073] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,
and heteroaryl groups, which are divalent bridging groups are
further referred to using the suffix-ene, e.g., alkylene,
alkenylene, alkynylene, carbocyclylene, heterocyclylene, arylene,
and heteroarylene.
[0074] The term "optionally substituted" refers to substituted or
unsubstituted.
[0075] Alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl,
and heteroaryl groups are optionally substituted (e.g.,
"substituted" or "unsubstituted" alkyl, "substituted" or
"unsubstituted" alkenyl, "substituted" or "unsubstituted" alkynyl,
"substituted" or "unsubstituted" carbocyclyl, "substituted" or
"unsubstituted" heterocyclyl, "substituted" or "unsubstituted" aryl
or "substituted" or "unsubstituted" heteroaryl group) if not
otherwise provided explicitly. In general, the term "substituted",
whether preceded by the term "optionally" or not, means that at
least one hydrogen present on a group (e.g., a carbon or nitrogen
atom) is replaced with a permissible substituent, e.g., a
substituent which upon substitution results in a stable compound,
e.g., a compound which does not spontaneously undergo
transformation such as by rearrangement, cyclization, elimination,
or other reaction. Unless otherwise indicated, a "substituted"
group has a substituent at one or more substitutable positions of
the group, and when more than one position in any given structure
is substituted, the substituent is either the same or different at
each position. The term "substituted" is contemplated to include
substitution with all permissible substituents of organic
compounds, any of the substituents described herein that results in
the formation of a stable compound. The present invention
contemplates any and all such combinations in order to arrive at a
stable compound. For purposes of this invention, heteroatoms such
as nitrogen may have hydrogen substituents and/or any suitable
substituent as described herein which satisfy the valencies of the
heteroatoms and results in the formation of a stable moiety.
[0076] Exemplary carbon atom substituents include, but are not
limited to, halogen, --CN, --NO.sub.2, --N.sub.3, --SO.sub.2H,
--SO.sub.3H, --OH, --OR.sup.aa, --ON(R.sup.bb).sub.2,
--N(R.sup.bb).sub.2, --N(R.sup.bb).sub.3.sup.+X.sup.-,
--N(OR.sup.cc)R.sup.bb, --C(.dbd.O)R.sup.aa, --CO.sub.2H, --CHO,
--C(OR.sup.cc).sub.2, --CO.sub.2.sup.aa, --OC(.dbd.O)R.sup.aa,
--OCO.sub.2R.sup.aa, --C(.dbd.O)N(R.sup.bb).sub.2,
--OC(.dbd.O)N(R.sup.bb).sub.2, --NR.sup.bbC(.dbd.O)R.sup.aa,
--NR.sup.bbCO.sub.2R.sup.aa, --NR.sup.bbC(.dbd.O)N(R.sup.bb).sub.2,
--C(.dbd.NR.sup.bb)R.sup.aa, --C(.dbd.NR.sup.bb)OR.sup.aa,
--OC(.dbd.NR.sup.bb)R.sup.aa, --OC(.dbd.NR.sup.bb)OR.sup.aa,
--C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--OC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--NR.sup.bbC(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--C(.dbd.O)NR.sup.bbSO.sub.2R.sup.aa, --NR.sup.bbSO.sub.2R.sup.aa,
--SO.sub.2N(R.sup.bb).sub.2, --SO.sub.2R.sup.aa,
--SO.sub.2OR.sup.aa, --OSO.sub.2R.sup.aa, --S(.dbd.O)R.sup.aa,
--OS(.dbd.O)R.sup.aa, --Si(R.sup.aa).sub.3,
--OSi(R.sup.aa).sub.3--C(.dbd.S)N(R.sup.bb).sub.2,
--C(.dbd.O)SR.sup.aa, --C(.dbd.S)SR.sup.aa, --SC(.dbd.S)SR.sup.aa,
--SC(.dbd.O)SR.sup.aa, --OC(.dbd.O)SR.sup.aa,
--SC(.dbd.O)OR.sup.aa, --SC(.dbd.O)R.sup.aa,
--P(.dbd.O).sub.2R.sup.aa, --OP(.dbd.O).sub.2R.sup.aa,
--P(.dbd.O)(R.sup.aa).sub.2, --OP(.dbd.O)(R.sup.aa).sub.2,
--OP(.dbd.O)(OR.sup.cc).sub.2, --P(.dbd.O).sub.2N(R.sup.bb).sub.2,
--OP(.dbd.O).sub.2N(R.sup.bb).sub.2, --P(.dbd.O)(NR.sup.bb).sub.2,
--OP(.dbd.O)(NR.sup.bb).sub.2,
--NR.sup.bbP(.dbd.O)(OR.sup.cc).sub.2,
--NR.sup.bbP(.dbd.O)(NR.sup.bb).sub.2, --P(R.sup.cc).sub.2,
--P(R.sup.cc).sub.3, --OP(R.sup.cc).sub.2, --OP(R.sup.cc).sub.3,
--B(R.sup.aa).sub.2, --B(OR.sup.cc).sub.2, --BR.sup.aa(OR.sup.cc),
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl,
wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
aryl, and heteroaryl is independently substituted with 0, 1, 2, 3,
4, or 5 R.sup.dd groups;
[0077] or two geminal hydrogens on a carbon atom are replaced with
the group .dbd.O, .dbd.S, .dbd.NN(R.sup.bb).sub.2,
.dbd.NNR.sup.bbC(.dbd.O)R.sup.aa,
.dbd.NNR.sup.bbC(.dbd.O)OR.sup.aa,
.dbd.NNR.sup.bbS(.dbd.O).sub.2R.sup.aa, .dbd.NR.sup.bb, or
.dbd.NOR.sup.cc;
[0078] each instance of R.sup.aa is, independently, selected from
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.aa groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0079] each instance of R.sup.bb is, independently, selected from
hydrogen, --OH, --OR.sup.aa, --N(R.sup.cc).sub.2, --CN,
--C(.dbd.O)R.sup.aa, --C(.dbd.O)N(R.sup.cc).sub.2,
--CO.sub.2R.sup.aa, --SO.sub.2R.sup.aa,
--C(.dbd.NR.sup.cc)OR.sup.aa, --C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2,
--SO.sub.2N(R.sup.cc).sub.2, --SO.sub.2R.sup.cc,
--SO.sub.2OR.sup.cc, --SOR.sup.aa, --C(.dbd.S)N(R.sup.cc).sub.2,
--C(.dbd.O)SR.sup.cc, --C(.dbd.S)SR.sup.cc,
--P(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O).sub.2N(R.sup.cc).sub.2, --P(.dbd.O)(NR.sup.cc).sub.2,
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.bb groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd
groups;
[0080] each instance of R.sup.cc is, independently, selected from
hydrogen, C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10
alkenyl, C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.cc groups are joined to form a 3-14 membered heterocyclyl or
5-14 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups;
each instance of R.sup.dd is, independently, selected from halogen,
--CN, --NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H, --OH,
--OR.sup.ee, --ON(R.sup.ff).sub.2, --N(R.sup.ff).sub.2,
--N(R.sup.ff).sub.3.sup.+X.sup.-, --N(OR.sup.ee)R.sup.ff,
--C(.dbd.O)R.sup.ee, --CO.sub.2H, --CO.sub.2R.sup.ee,
--OC(.dbd.O)R.sup.ee, --OCO.sub.2R.sup.ee,
--C(.dbd.O)N(R.sup.ff).sub.2, --OC(.dbd.O)N(R.sup.ff).sub.2,
--NR.sup.ffC(.dbd.O)R.sup.ee, --NR.sup.ffCO.sub.2R.sup.ee,
--NR.sup.ffC(.dbd.O)N(R.sup.ff).sub.2,
--C(.dbd.NR.sup.ff)OR.sup.ee, --OC(.dbd.NR.sup.ff)R.sup.ee,
--OC(.dbd.NR.sup.ff)OR.sup.ee,
--C(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--OC(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--NR.sup.ffC(.dbd.NR.sup.ff)N(R.sup.ff).sub.2,
--NR.sup.ffSO.sub.2R.sup.ee, --SO.sub.2N(R.sup.ff).sub.2,
--SO.sub.2R.sup.ee, --SO.sub.2R.sup.ee, --OSO.sub.2R.sup.ee,
--S(.dbd.O)R.sup.ee, --Si(R.sup.ee).sub.3, --OSi(R.sup.ee).sub.3,
--C(.dbd.S)N(R.sup.ff).sub.2, --C(.dbd.O)SR.sup.ee,
--C(.dbd.S)SR.sup.ee, --SC(.dbd.S)SR.sup.ee,
--P(.dbd.O).sub.2R.sup.ee, --P(.dbd.O)(R.sup.ee).sub.2,
--OP(.dbd.O)(R.sup.ee).sub.2, --OP(.dbd.O)(OR.sup.ee).sub.2,
C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, 3-10 membered
heterocyclyl, C.sub.6-10 aryl, 5-10 membered heteroaryl, wherein
each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and
heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5
R.sup.gg groups, or two geminal R.sup.dd substituents can be joined
to form .dbd.O or .dbd.S;
[0081] each instance of R.sup.ee is, independently, selected from
C.sub.1-6 alkyl, C.sub.1-5 perhaloalkyl, C.sub.2-6 alkenyl,
C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 3-10
membered heterocyclyl, and 3-10 membered heteroaryl, wherein each
alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, and
heteroaryl is independently substituted with 0, 1, 2, 3, 4, or 5
R.sup.gg groups;
[0082] each instance of R.sup.ff is, independently, selected from
hydrogen, C.sub.1-6 alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6
alkenyl, C.sub.2-6 alkynyl, C.sub.3-10 carbocyclyl, 3-10 membered
heterocyclyl, C.sub.6-10 aryl and 5-10 membered heteroaryl, or two
R.sup.ff groups are joined to form a 3-10 membered heterocyclyl or
5-10 membered heteroaryl ring, wherein each alkyl, alkenyl,
alkynyl, carbocyclyl, heterocyclyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.gg groups;
and
[0083] each instance of R.sup.gg is, independently, halogen, --CN,
--NO.sub.2, --N.sub.3, --SO.sub.2H, --SO.sub.3H, --OH, --OC.sub.1-6
alkyl, --ON(C.sub.1-6 alkyl).sub.2, --N(C.sub.1-6 alkyl).sub.2,
--N(C.sub.1-6 alkyl).sub.3.sup.+X.sup.-, --NH(C.sub.1-6
alkyl).sub.2.sup.+X.sup.-, --NH.sub.2(C.sub.1-6
alkyl).sup.+X.sup.-, --NH.sub.3.sup.+X.sup.-, --N(OC.sub.1-6
alkyl)(C.sub.1-6 alkyl), --N(OH)(C.sub.1-6 alkyl), --NH(OH),
--SC.sub.1-6 alkyl, --SS(C.sub.1-6 alkyl), --C(.dbd.O)(C.sub.1-6
alkyl), --CO.sub.2H, --CO.sub.2(C.sub.1-6 alkyl),
--OC(.dbd.O)(C.sub.1-6 alkyl), --OCO.sub.2(C.sub.1-6 alkyl),
--C(.dbd.O)NH.sub.2, --C(.dbd.O)N(C.sub.1-6 alkyl).sub.2,
--OC(.dbd.O)NH(C.sub.1-6 alkyl), --NHC(.dbd.O)(C.sub.1-6 alkyl),
--N(C.sub.1-6 alkyl)C(.dbd.O)(C.sub.1-6 alkyl),
--NHCO.sub.2(C.sub.1-6 alkyl), --NHC(.dbd.O)N(C.sub.1-6
alkyl).sub.2, --NHC(.dbd.O)NH(C.sub.1-6 alkyl),
--NHC(.dbd.O)NH.sub.2, --C(.dbd.NH)O(C.sub.1-6 alkyl),
--OC(.dbd.NH)(C.sub.1-6 alkyl), --OC(.dbd.NH)OC.sub.1-6 alkyl,
--C(.dbd.NH)N(C.sub.1-6 alkyl).sub.2, --C(.dbd.NH)NH(C.sub.1-6
alkyl), --C(.dbd.NH)NH.sub.2, --OC(.dbd.NH)N(C.sub.1-6
alkyl).sub.2, --OC(NH)NH(C.sub.1-6 alkyl), --OC(NH)NH.sub.2,
--NHC(NH)N(C.sub.1-6 alkyl).sub.2, --NHC(.dbd.NH)NH.sub.2,
--NHSO.sub.2(C.sub.1-6 alkyl), --SO.sub.2N(C.sub.1-6 alkyl).sub.2,
--SO.sub.2NH(C.sub.1-6 alkyl), --SO.sub.2NH.sub.2,
--SO.sub.2C.sub.1-6 alkyl, --SO.sub.2OC.sub.1-6 alkyl,
--OSO.sub.2C.sub.1-5 alkyl, --SOC.sub.1-6 alkyl, --Si(C.sub.1-6
alkyl).sub.3, --OSi(C.sub.1-6 alkyl).sub.3-C(.dbd.S)N(C.sub.1-6
alkyl).sub.2, C(.dbd.S)NH(C.sub.1-6 alkyl), C(.dbd.S)NH.sub.2,
--C(.dbd.O)S(C.sub.1-6 alkyl), --C(.dbd.S)SC.sub.1-6 alkyl,
--SC(.dbd.S)SC.sub.1-6 alkyl, --P(.dbd.O).sub.2(C.sub.1-6 alkyl),
--P(.dbd.O)(C.sub.1-6 alkyl).sub.2, --OP(.dbd.O)(C.sub.1-6
alkyl).sub.2, --OP(.dbd.O)(OC.sub.1-6 alkyl).sub.2, C.sub.1-6
alkyl, C.sub.1-6 perhaloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, C.sub.3-10 carbocyclyl, C.sub.6-10 aryl, 3-10 membered
heterocyclyl, 5-10 membered heteroaryl; or two geminal R.sup.gg
substituents can be joined to form .dbd.O or .dbd.S; wherein X is a
counterion.
[0084] "Halo" or "halogen" refers to fluorine (fluoro, --F),
chlorine (chloro, --Cl), bromine (bromo, --Br), or iodine (iodo,
--I).
[0085] "Acyl" refers to a moiety selected from the group consisting
of --C(.dbd.O)R.sup.aa, --CHO, --CO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.bb)OR.sup.aa, --C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--C(.dbd.O)NR.sup.bbSO.sub.2R.sup.aa, --C(.dbd.S)N(R.sup.bb).sub.2,
--C(.dbd.O)SR.sup.aa, or --C(.dbd.S)SR.sup.aa, wherein R.sup.aa and
R.sup.bb are as defined herein.
[0086] Nitrogen atoms can be substituted or unsubstituted as
valency permits, and include primary, secondary, tertiary, and
quaternary nitrogen atoms. Exemplary nitrogen atom substituents
include, but are not limited to, hydrogen, --OH, --OR.sup.aa,
--N(R.sup.cc).sub.2, --CN, --C(.dbd.O)R.sup.aa,
--C(.dbd.O)N(R.sup.cc).sub.2, --CO.sub.2R.sup.aa,
--SO.sub.2R.sup.aa, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.cc)OR.sup.aa, --C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2,
--SO.sub.2N(R.sup.cc).sub.2, --SO.sub.2R.sup.cc,
--SO.sub.2OR.sup.cc, --SOR.sup.aa, --C(.dbd.S)N(R.sup.cc).sub.2,
--C(.dbd.O)SR.sup.cc, --C(.dbd.S)SR.sup.cc,
--P(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O).sub.2N(R.sup.cc).sub.2, --P(.dbd.O)(NR.sup.cc).sub.2,
C.sub.1-10 alkyl, C.sub.1-10 perhaloalkyl, C.sub.2-10 alkenyl,
C.sub.2-10 alkynyl, C.sub.3-10 carbocyclyl, 3-14 membered
heterocyclyl, C.sub.6-14 aryl, and 5-14 membered heteroaryl, or two
R.sup.cc groups attached to a nitrogen atom are joined to form a
3-14 membered heterocyclyl or 5-14 membered heteroaryl ring,
wherein each alkyl, alkenyl, alkynyl, carbocyclyl, heterocyclyl,
aryl, and heteroaryl is independently substituted with 0, 1, 2, 3,
4, or 5 R.sup.dd groups, and wherein R.sup.aa, R.sup.bbR.sup.cc,
and R.sup.dd are as defined above.
[0087] In certain embodiments, the substituent present on a
nitrogen atom is a nitrogen protecting group (also referred to as
an amino protecting group). Nitrogen protecting groups include, but
are not limited to, --OH, --OR.sup.aa, --N(R.sup.cc).sub.2,
--C(.dbd.O)R.sup.aa, --C(.dbd.O)N(R.sup.cc).sub.2,
--CO.sub.2R.sup.aa, --SO.sub.2R.sup.aa,
--C(.dbd.NR.sup.cc)R.sup.aa, --C(.dbd.NR.sup.cc)OR.sup.aa,
--C(.dbd.NR.sup.cc)N(R.sup.cc).sub.2, --SO.sub.2N(R.sup.cc).sub.2,
--SO.sub.2R.sup.cc, --SO.sub.2OR.sup.cc, --SOR.sup.aa,
--C(.dbd.S)N(R.sup.cc).sub.2, --C(.dbd.O)SR.sup.cc,
--C(.dbd.S)SR.sup.cc, C.sub.1-10 alkyl (e.g., aralkyl,
heteroaralkyl), C.sub.2-10 alkenyl, C.sub.2-10 alkynyl, C.sub.3-10
carbocyclyl, 3-14 membered heterocyclyl, C.sub.6-14 aryl, and 5-14
membered heteroaryl groups, wherein each alkyl, alkenyl, alkynyl,
carbocyclyl, heterocyclyl, aralkyl, aryl, and heteroaryl is
independently substituted with 0, 1, 2, 3, 4, or 5 R.sup.dd groups,
and wherein R.sup.aa, R.sup.bb, R.sup.cc and R.sup.dd are as
defined herein. Nitrogen protecting groups are well known in the
art and include those described in detail in Protecting Groups in
Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3.sup.rd
edition, John Wiley & Sons, 1999, incorporated herein by
reference.
[0088] For example, nitrogen protecting groups such as amide groups
(e.g., --C(.dbd.O)R.sup.aa) include, but are not limited to,
formamide, acetamide, chloroacetamide, trichloroacetamide,
trifluoroacetamide, phenylacetamide, 3-phenylpropanamide,
picolinamide, 3-pyridylcarboxamide, N-benzoylphenylalanyl
derivative, benzamide, p-phenylbenzamide, o-nitophenylacetamide,
o-nitrophenoxyacetamide, acetoacetamide,
(N'-dithiobenzyloxyacylamino)acetamide,
3-(p-hydroxyphenyl)propanamide, 3-(o-nitrophenyl)propanamide,
2-methyl-2-(o-nitrophenoxy)propanamide,
2-methyl-2-(o-phenylazophenoxy)propanamide, 4-chlorobutanamide,
3-methyl-3-nitrobutanamide, o-nitrocinnamide, N-acetylmethionine
derivative, o-nitrobenzamide, and
o-(benzoyloxymethyl)benzamide.
[0089] Nitrogen protecting groups such as carbamate groups (e.g.,
--C(.dbd.O)OR.sup.aa) include, but are not limited to, methyl
carbamate, ethyl carbamante, 9-fluorenylmethyl carbamate (Fmoc),
9-(2-sulfo)fluorenylmethyl carbamate,
9-(2,7-dibromo)fluoroenylmethyl carbamate,
2,7-di-t-butyl-[9-(10,10-dioxo-10,10,10,10,10-tetrahydrothioxanthyl)]meth-
yl carbamate (DBD-Tmoc), 4-methoxyphenacyl carbamate (Phenoc),
2,2,2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl
carbamate (Teoc), 2-phenylethyl carbamate (hZ),
1-(1-adamantyl)-1-methylethyl carbamate (Adpoc),
1,1-dimethyl-2-haloethyl carbamate, 1,1-dimethyl-2,2-dibromoethyl
carbamate (DB-t-BOC), 1,1-dimethyl-2,2,2-trichloroethyl carbamate
(TCBOC), 1-methyl-1-(4-biphenylyl)ethyl carbamate (Bpoc),
1-(3,5-di-t-butylphenyl)-1-methylethyl carbamate (t-Bumeoc), 2-(2'-
and 4'-pyridyl)ethyl carbamate (Pyoc),
2-(N,N-dicyclohexylcarboxamido)ethyl carbamate, t-butyl carbamate
(BOC or Boc), 1-adamantyl carbamate (Adoc), vinyl carbamate (Voc),
allyl carbamate (Alloc), 1-isopropylallyl carbamate (Ipaoc),
cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc),
8-quinolyl carbamate, N-hydroxypiperidinyl carbamate, alkyldithio
carbamate, benzyl carbamate (Cbz), p-methoxybenzyl carbamate (Moz),
p-nitobenzyl carbamate, p-bromobenzyl carbamate, p-chlorobenzyl
carbamate, 2,4-dichlorobenzyl carbamate, 4-methylsulfinylbenzyl
carbamate (Msz), 9-anthrylmethyl carbamate, diphenylmethyl
carbamate, 2-methylthioethyl carbamate, 2-methylsulfonylethyl
carbamate, 2-(p-toluenesulfonyl)ethyl carbamate,
[2-(1,3-dithianyl)]methyl carbamate (Dmoc), 4-methylthiophenyl
carbamate (Mtpc), 2,4-dimethylthiophenyl carbamate (Bmpc),
2-phosphonioethyl carbamate (Peoc), 2-triphenylphosphonioisopropyl
carbamate (Ppoc), 1,1-dimethyl-2-cyanoethyl carbamate,
m-chloro-p-acyloxybenzyl carbamate, p-(dihydroxyboryl)benzyl
carbamate, 5-benzisoxazolylmethyl carbamate,
2-(trifluoromethyl)-6-chromonylmethyl carbamate (Tcroc),
m-nitrophenyl carbamate, 3,5-dimethoxybenzyl carbamate,
o-nitrobenzyl carbamate, 3,4-dimethoxy-6-nitrobenzyl carbamate,
phenyl(o-nitrophenyl)methyl carbamate, t-amyl carbamate, S-benzyl
thiocarbamate, p-cyanobenzyl carbamate, cyclobutyl carbamate,
cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethyl
carbamate, p-decyloxybenzyl carbamate, 2,2-dimethoxyacylvinyl
carbamate, o-(N,N-dimethylcarboxamido)benzyl carbamate,
1,1-dimethyl-3-(N,N-dimethylcarboxamido)propyl carbamate,
1,1-dimethylpropynyl carbamate, di(2-pyridyl)methyl carbamate,
2-furanylmethyl carbamate, 2-iodoethyl carbamate, isoborynl
carbamate, isobutyl carbamate, isonicotinyl carbamate,
p-(p'-methoxyphenylazo)benzyl carbamate, 1-methylcyclobutyl
carbamate, 1-methylcyclohexyl carbamate,
1-methyl-1-cyclopropylmethyl carbamate,
1-methyl-1-(3,5-dimethoxyphenyl)ethyl carbamate,
1-methyl-1-(p-phenylazophenyl)ethyl carbamate,
1-methyl-1-phenylethyl carbamate, 1-methyl-1-(4-pyridyl)ethyl
carbamate, phenyl carbamate, p-(phenylazo)benzyl carbamate,
2,4,6-tri-t-butylphenyl carbamate, 4-(trimethylammonium)benzyl
carbamate, and 2,4,6-trimethylbenzyl carbamate.
[0090] Nitrogen protecting groups such as sulfonamide groups (e.g.,
--S(.dbd.O).sub.2R.sup.aa) include, but are not limited to,
p-toluenesulfonamide (Ts), benzenesulfonamide,
2,3,6,-trimethyl-4-methoxybenzenesulfonamide (Mtr),
2,4,6-trimethoxybenzenesulfonamide (Mtb),
2,6-dimethyl-4-methoxybenzenesulfonamide (Pme),
2,3,5,6-tetramethyl-4-methoxybenzenesulfonamide (Mte),
4-methoxybenzenesulfonamide (Mbs),
2,4,6-trimethylbenzenesulfonamide (Mts),
2,6-dimethoxy-4-methylbenzenesulfonamide (iMds),
2,2,5,7,8-pentamethylchroman-6-sulfonamide (Pmc),
methanesulfonamide (Ms), P-trimethylsilylethanesulfonamide (SES),
9-anthracenesulfonamide,
4-(4',8'-dimethoxynaphthylmethyl)benzenesulfonamide (DNMBS),
benzylsulfonamide, trifluoromethylsulfonamide, and
phenacylsulfonamide.
[0091] Other nitrogen protecting groups include, but are not
limited to, phenothiazinyl-(10)-acyl derivative,
N'-p-toluenesulfonylaminoacyl derivative, N'-phenylaminothioacyl
derivative, N-benzoylphenylalanyl derivative, N-acetylmethionine
derivative, 4,5-diphenyl-3-oxazolin-2-one, N-phthalimide,
N-dithiasuccinimide (Dts), N-2,3-diphenylmaleimide,
N-2,5-dimethylpyrrole, N-1,1,4,4-tetramethyldisilylazacyclopentane
adduct (STABASE), 5-substituted
1,3-dimethyl-1,3,5-triazacyclohexan-2-one, 5-substituted
1,3-dibenzyl-1,3,5-triazacyclohexan-2-one, 1-substituted
3,5-dinitro-4-pyridone, N-methylamine, N-allylamine,
N-[2-(trimethylsilyl)ethoxy]methylamine (SEM),
N-3-acetoxypropylamine,
N-(1-isopropyl-4-nitro-2-oxo-3-pyroolin-3-yl)amine, quaternary
ammonium salts, N-benzylamine, N-di(4-methoxyphenyl)methylamine,
N-5-dibenzosuberylamine, N-triphenylmethylamine (Tr),
N-[(4-methoxyphenyl)diphenylmethyl]amine (MMTr),
N-9-phenylfluorenylamine (PhF),
N-2,7-dichloro-9-fluorenylmethyleneamine, N-ferrocenylmethylamino
(Fcm), N-2-picolylamino N'-oxide, N-1,1-dimethylthiomethyleneamine,
N-benzylideneamine, N-p-methoxybenzylideneamine,
N-diphenylmethyleneamine, N-[(2-pyridyl)mesityl]methyleneamine,
N--(N',N'-dimethylaminomethylene)amine, N,N'-isopropylidenediamine,
N-p-nitrobenzylideneamine, N-salicylideneamine,
N-5-chlorosalicylideneamine,
N-(5-chloro-2-hydroxyphenyl)phenylmethyleneamine,
N-cyclohexylideneamine, N-(5,5-dimethyl-3-oxo-1-cyclohexenyl)amine,
N-borane derivative, N-diphenylborinic acid derivative,
N-[phenyl(pentaacylchromium- or tungsten)acyl]amine, N-copper
chelate, N-zinc chelate, N-nitroamine, N-nitrosoamine, amine
N-oxide, diphenylphosphinamide (Dpp), dimethylthiophosphinamide
(Mpt), diphenylthiophosphinamide (Ppt), dialkyl phosphoramidates,
dibenzyl phosphoramidate, diphenyl phosphoramidate,
benzenesulfenamide, o-nitrobenzenesulfenamide (Nps),
2,4-dinitrobenzenesulfenamide, pentachlorobenzenesulfenamide,
2-nitro-4-methoxybenzenesulfenamide, triphenylmethylsulfenamide,
and 3-nitropyridinesulfenamide (Npys).
[0092] In certain embodiments, the substituent present on an oxygen
atom is an oxygen protecting group (also referred to as a hydroxyl
protecting group). Oxygen protecting groups include, but are not
limited to, --R.sup.aa, --N(R.sup.bb).sub.2, --C(.dbd.O)SR.sup.aa,
--C(.dbd.O)R.sup.aa, --CO.sub.2R.sup.aa,
--C(.dbd.O)N(R.sup.bb).sub.2, --C(.dbd.NR.sup.bb)R.sup.aa,
--C(.dbd.NR.sup.bb)OR.sup.aa, --C(.dbd.NR.sup.bb)N(R.sup.bb).sub.2,
--S(.dbd.O)R.sup.aa, --SO.sub.2R.sup.aa, --Si(R.sup.aa).sub.3,
--P(R.sup.cc).sub.2, --P(R.sup.cc).sub.3,
--P(.dbd.O).sub.2R.sup.aa, --P(.dbd.O)(R.sup.aa).sub.2,
--P(.dbd.O)(OR.sup.cc).sub.2, --P(.dbd.O).sub.2N(R.sup.bb).sub.2,
and --P(.dbd.O)(NR.sup.bb).sub.2, wherein R.sup.aa, R.sup.bb, and
R.sup.cc are as defined herein. Oxygen protecting groups are well
known in the art and include those described in detail in
Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M.
Wuts, 3.sup.rd edition, John Wiley & Sons, 1999, incorporated
herein by reference.
[0093] Exemplary oxygen protecting groups include, but are not
limited to, methyl, methoxylmethyl (MOM), tert-butoxycarbonyl,
methylthiomethyl (MTM), t-butylthiomethyl,
(phenyldimethylsilyl)methoxymethyl (SMOM), benzyloxymethyl (BOM),
p-methoxybenzyloxymethyl (PMBM), (4-methoxyphenoxy)methyl (p-AOM),
guaiacolmethyl (GUM), t-butoxymethyl, 4-pentenyloxymethyl (POM),
siloxymethyl, 2-methoxyethoxymethyl (MEM),
2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl,
2-(trimethylsilyl)ethoxymethyl (SEMOR), tetrahydropyranyl (THP),
3-bromotetrahydropyranyl, tetrahydrothiopyranyl,
1-methoxycyclohexyl, 4-methoxytetrahydropyranyl (MTHP),
4-methoxytetrahydrothiopyranyl, 4-methoxytetrahydrothiopyranyl
S,S-dioxide, 1-[(2-chloro-4-methyl)phenyl]-4-methoxypiperidin-4-yl
(CTMP), 1,4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl,
2,3,3a,4,5,6,7,7a-octahydro-7,8,8-trimethyl-4,7-methanobenzofuran-2-yl,
1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 1-methyl-1-methoxyethyl,
1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl,
2,2,2-trichloroethyl, 2-trimethylsilylethyl,
2-(phenylselenyl)ethyl, t-butyl, allyl, p-chlorophenyl,
p-methoxyphenyl, 2,4-dinitrophenyl, benzyl (Bn), p-methoxybenzyl,
3,4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, p-halobenzyl,
2,6-dichlorobenzyl, p-cyanobenzyl, p-phenylbenzyl, 2-picolyl,
4-picolyl, 3-methyl-2-picolyl N-oxido, diphenylmethyl,
p,p'-dinitrobenzhydryl, 5-dibenzosuberyl, triphenylmethyl,
.alpha.-naphthyldiphenylmethyl, p-methoxyphenyldiphenylmethyl,
di(p-methoxyphenyl)phenylmethyl, tri(p-methoxyphenyl)methyl,
4-(4'-bromophenacyloxyphenyl)diphenylmethyl,
4,4',4''-tris(4,5-dichlorophthalimidophenyl)methyl,
4,4',4''-tris(levulinoyloxyphenyl)methyl,
4,4',4''-tris(benzoyloxyphenyl)methyl,
3-(imidazol-1-yl)bis(4',4''-dimethoxyphenyl)methyl,
1,1-bis(4-methoxyphenyl)-1'-pyrenylmethyl, 9-anthryl,
9-(9-phenyl)xanthenyl, 9-(9-phenyl-10-oxo)anthryl,
1,3-benzodisulfuran-2-yl, benzisothiazolyl S,S-dioxido,
trimethylsilyl (TMS), triethylsilyl (TES), triisopropylsilyl
(TIPS), dimethylisopropylsilyl (IPDMS), diethylisopropylsilyl
(DEIPS), dimethylthexylsilyl, t-butyldimethylsilyl (TBDMS),
t-butyldiphenylsilyl (TBDPS), tribenzylsilyl, tri-p-xylylsilyl,
triphenylsilyl, diphenylmethylsilyl (DPMS),
t-butylmethoxyphenylsilyl (TBMPS), formate, benzoylformate,
acetate, chloroacetate, dichloroacetate, trichloroacetate,
trifluoroacetate, methoxyacetate, triphenylmethoxyacetate,
phenoxyacetate, p-chlorophenoxyacetate, 3-phenylpropionate,
4-oxopentanoate (levulinate), 4,4-(ethylenedithio)pentanoate
(levulinoyldithioacetal), pivaloate, adamantoate, crotonate,
4-methoxycrotonate, benzoate, p-phenylbenzoate,
2,4,6-trimethylbenzoate (mesitoate), alkyl methyl carbonate,
9-fluorenylmethyl carbonate (Fmoc), alkyl ethyl carbonate, alkyl
2,2,2-trichloroethyl carbonate (Troc), 2-(trimethylsilyl)ethyl
carbonate (TMSEC), 2-(phenylsulfonyl) ethyl carbonate (Psec),
2-(triphenylphosphonio) ethyl carbonate (Peoc), alkyl isobutyl
carbonate, alkyl vinyl carbonate, alkyl allyl carbonate, alkyl
p-nitrophenyl carbonate, alkyl benzyl carbonate, alkyl
p-methoxybenzyl carbonate, alkyl 3,4-dimethoxybenzyl carbonate,
alkyl o-nitrobenzyl carbonate, alkyl p-nitrobenzyl carbonate, alkyl
S-benzyl thiocarbonate, 4-ethoxy-1-napththyl carbonate, methyl
dithiocarbonate, 2-iodobenzoate, 4-azidobutyrate,
4-nitro-4-methylpentanoate, o-(dibromomethyl)benzoate,
2-formylbenzenesulfonate, 2-(methylthiomethoxy)ethyl,
4-(methylthiomethoxy)butyrate, 2-(methylthiomethoxymethyl)benzoate,
2,6-dichloro-4-methylphenoxyacetate,
2,6-dichloro-4-(1,1,3,3-tetramethylbutyl)phenoxyacetate,
2,4-bis(1,1-dimethylpropyl)phenoxyacetate, chlorodiphenylacetate,
isobutyrate, monosuccinoate, (E)-2-methyl-2-butenoate,
o-(methoxyacyl)benzoate, o-naphthoate, nitrate, alkyl
N,N,N',N'-tetramethylphosphorodiamidate, alkyl N-phenylcarbamate,
borate, dimethylphosphinothioyl, alkyl 2,4-dinitrophenylsulfenate,
sulfate, methanesulfonate (mesylate), benzylsulfonate, and tosylate
(Ts).
[0094] A "hydrocarbon chain" refers to a substituted or
unsubstituted divalent alkyl, alkenyl, or alkynyl group. A
hydrocarbon chain includes (1) one or more chains of carbon atoms
immediately between the two radicals of the hydrocarbon chain; (2)
optionally one or more hydrogen atoms on the chain(s) of carbon
atoms; and (3) optionally one or more substituents ("non-chain
substituents," which are not hydrogen) on the chain(s) of carbon
atoms. A chain of carbon atoms consists of consecutively connected
carbon atoms ("chain atoms") and does not include hydrogen atoms or
heteroatoms. However, a non-chain substituent of a hydrocarbon
chain may include any atoms, including hydrogen atoms, carbon
atoms, and heteroatoms. For example, hydrocarbon chain
--C.sup.AH(C.sup.BH.sub.2C.sup.CH.sub.3)-- includes one chain atom
C.sup.A, one hydrogen atom on C.sup.A, and non-chain substituent
--(C.sup.BH.sub.2C.sup.CH.sub.3). The term "C.sub.x hydrocarbon
chain," wherein x is a positive integer, refers to a hydrocarbon
chain that includes x number of chain atom(s) between the two
radicals of the hydrocarbon chain. If there is more than one
possible value of x, the smallest possible value of x is used for
the definition of the hydrocarbon chain. For example,
--CH(C.sub.2H.sub.5)-- is a C.sub.1 hydrocarbon chain, and
##STR00007##
is a C.sub.3 hydrocarbon chain. When a range of values is used, the
meaning of the range is as described herein. For example, a
C.sub.3-10 hydrocarbon chain refers to a hydrocarbon chain where
the number of chain atoms of the shortest chain of carbon atoms
immediately between the two radicals of the hydrocarbon chain is 3,
4, 5, 6, 7, 8, 9, or 10. A hydrocarbon chain may be saturated
(e.g., --(CH.sub.2).sub.4--). A hydrocarbon chain may also be
unsaturated and include one or more C.dbd.C and/or C.ident.C bonds
anywhere in the hydrocarbon chain. For instance,
--CH.dbd.CH--(CH.sub.2).sub.2--, --CH.sub.2--C.ident.C--CH.sub.2--,
and --C.ident.C--CH.dbd.CH-- are all examples of a unsubstituted
and unsaturated hydrocarbon chain. In certain embodiments, the
hydrocarbon chain is unsubstituted (e.g., --C.ident.C-- or
--(CH.sub.2).sub.4--). In certain embodiments, the hydrocarbon
chain is substituted (e.g., --CH(C.sub.2H.sub.5)-- and
--CF.sub.2--). Any two substituents on the hydrocarbon chain may be
joined to form an optionally substituted carbocyclyl, optionally
substituted heterocyclyl, optionally substituted aryl, or
optionally substituted heteroaryl ring. For instance,
##STR00008##
and are all examples of a hydrocarbon chain. In contrast, in
certain embodiments,
##STR00009##
are not within the scope of the hydrocarbon chains described
herein. When a chain atom of a C.sub.x hydrocarbon chain is
replaced with a heteroatom, the resulting group is referred to as a
C.sub.x hydrocarbon chain wherein a chain atom is replaced with a
heteroatom, as opposed to a C.sub.x-1 hydrocarbon chain. For
example,
##STR00010##
is a C.sub.3 hydrocarbon chain wherein one chain atom is replaced
with an oxygen atom.
[0095] A "counterion" or "anionic counterion" is a negatively
charged group associated with a positively charged group in order
to maintain electronic neutrality. An anionic counterion may be
monovalent (i.e., including one formal negative charge). An anionic
counterion may also be multivalent (i.e., including more than one
formal negative charge), such as divalent or trivalent. Exemplary
counterions include halide ions (e.g., F.sup.-, Cl.sup.-, Br.sup.-,
I.sup.-), NO.sub.3.sup.-, ClO.sub.4.sup.-, OH.sup.-,
H.sub.2PO.sub.4.sup.-, HCO.sub.3.sup.-, HSO.sub.4.sup.-, sulfonate
ions (e.g., methansulfonate, trifluoromethanesulfonate,
p-toluenesulfonate, benzenesulfonate, 10-camphor sulfonate,
naphthalene-2-sulfonate, naphthalene-1-sulfonic acid-5-sulfonate,
ethan-1-sulfonic acid-2-sulfonate, and the like), carboxylate ions
(e.g., acetate, propanoate, benzoate, glycerate, lactate, tartrate,
glycolate, gluconate, and the like), BF.sub.4.sup.-,
PF.sub.4.sup.-, PF.sub.6.sup.-, AsF.sub.6.sup.-, SbF.sub.6.sup.-,
B[3,5-(CF.sub.3).sub.2C.sub.6H.sub.3].sub.4].sup.-,
B(C.sub.6F.sub.5).sub.4.sup.-, BPh.sub.4.sup.-,
Al(OC(CF.sub.3).sub.3).sub.4.sup.-, and carborane anions (e.g.,
CB.sub.11H.sub.12.sup.- or (HCB.sub.11Me.sub.5Br.sub.6).sup.-).
Exemplary counterions which may be multivalent include
CO.sub.3.sup.2-, HPO.sub.4.sup.2-, PO.sub.4.sup.3-,
B.sub.4O.sub.7.sup.2-, SO.sub.4.sup.2-, S.sub.2O.sub.3.sup.2-,
carboxylate anions (e.g., tartrate, citrate, fumarate, maleate,
malate, malonate, gluconate, succinate, glutarate, adipate,
pimelate, suberate, azelate, sebacate, salicylate, phthalates,
aspartate, glutamate, and the like), and carboranes.
[0096] The term "salt" refers to ionic compounds that result from
the neutralization reaction of an acid and a base. A salt is
composed of one or more cations (positively charged ions) and one
or more anions (negative ions) so that the salt is electrically
neutral (without a net charge). Salts of the compounds of this
invention include those derived from inorganic and organic acids
and bases. Examples of acid addition salts are salts of an amino
group formed with inorganic acids such as hydrochloric acid,
hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric
acid, or with organic acids such as acetic acid, oxalic acid,
maleic acid, tartaric acid, citric acid, succinic acid, or malonic
acid or by using other methods known in the art such as ion
exchange. Other salts include adipate, alginate, ascorbate,
aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate,
camphorate, camphorsulfonate, citrate, cyclopentanepropionate,
digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate,
glucoheptonate, glycerophosphate, gluconate, hemisulfate,
heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate,
lactobionate, lactate, laurate, lauryl sulfate, malate, maleate,
malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate,
nitrate, oleate, oxalate, palmitate, pamoate, pectinate,
persulfate, 3-phenylpropionate, phosphate, picrate, pivalate,
propionate, stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline
earth metal, ammonium and N.sup.+(C.sub.1-6 alkyl).sub.4 salts.
Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium, and the like. Further salts
include ammonium, quaternary ammonium, and amine cations formed
using counterions such as halide, hydroxide, carboxylate, sulfate,
phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.
[0097] The term "pharmaceutically acceptable salt" refers to those
salts which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and
the like, and are commensurate with a reasonable benefit/risk
ratio. Pharmaceutically acceptable salts are well known in the art.
For example, Berge et al., describe pharmaceutically acceptable
salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19,
incorporated herein by reference. Pharmaceutically acceptable salts
of the compounds of this disclosure include those derived from
suitable inorganic and organic acids and bases. Examples of
pharmaceutically acceptable, nontoxic acid addition salts are salts
of an amino group formed with inorganic acids such as hydrochloric
acid, hydrobromic acid, phosphoric acid, sulfuric acid, and
perchloric acid or with organic acids such as acetic acid, oxalic
acid, maleic acid, tartaric acid, citric acid, succinic acid, or
malonic acid or by using other methods known in the art such as ion
exchange. Other pharmaceutically acceptable salts include adipate,
alginate, ascorbate, aspartate, benzenesulfonate, benzoate,
bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate,
cyclopentanepropionate, digluconate, dodecylsulfate,
ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Salts derived from appropriate bases include alkali metal, alkaline
earth metal, ammonium and N.sup.+(C.sub.1-4 alkyl).sub.4.sup.-
salts. Representative alkali or alkaline earth metal salts include
sodium, lithium, potassium, calcium, magnesium, and the like.
Further pharmaceutically acceptable salts include, when
appropriate, nontoxic ammonium, quaternary ammonium, and amine
cations formed using counterions such as halide, hydroxide,
carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate,
and aryl sulfonate.
[0098] The term "lipophilic" or "hydrophobic" refers to the ability
of a compound to dissolve, or the ability of a moiety of a compound
to assist the compound in dissolving in fats, oils, lipids, and/or
non-polar solvents (e.g., hexane or toluene). Lipophilic moieties
include, but are not limited to, substituted or unsubstituted,
branched or unbranched alkyl groups having 1 to 50 carbon atoms. In
certain embodiments, the lipophilic moiety is an alkyl group
including at least 1, at least 6, at least 12, at least 18, at
least 24, at least 36, or at least 50 carbon atoms. In certain
embodiments, the lipophilic moiety is an alkyl group including at
most 50, at most 36, at most 24, at most 18, at most 12, or at most
6 carbon atoms. Combinations of the above-referenced ranges (e.g.,
at least 1 and at most about 24 carbon atoms) are also within the
scope of the disclosure. In certain embodiments, the lipophilic
moiety is unsubstituted alkyl. In certain embodiments, the
lipophilic moiety is unsubstituted and unbranched alkyl. In certain
embodiments, the lipophilic moiety is unsubstituted and unbranched
C.sub.1-24 alkyl. In certain embodiments, the lipophilic moiety is
unsubstituted and unbranched C.sub.6-24 alkyl. In certain
embodiments, the lipophilic moiety is unsubstituted and unbranched
C.sub.12-24 alkyl.
[0099] The term "polymer" refers to a compound comprising eleven or
more covalently connected repeating units. In certain embodiments,
a polymer is naturally occurring. In certain embodiments, a polymer
is synthetic (i.e., not naturally occurring).
[0100] The term "polydispersity" refers to a measure of the
distribution of molecular size in a mixture (e.g., a mixture of
polymers), e.g., as determined by a chromatographic method, such as
gel permeation chromatography or size exclusion chromatography, or
through dynamic light scattering.
[0101] An "elastomer" is a polymer that displays rubber-like
elasticity.
[0102] A "thermoplastic elastomer" is an elastomer comprising a
thermoreversible network.
[0103] The "molecular weight" of a monovalent moiety --U is
calculated by subtracting 1 from the molecular weight of the
compound U--H. The "molecular weight" of a divalent moiety --V-- is
calculated by subtracting 2 from the molecular weight of the
compound H--V--H.
[0104] The term "small molecule" refers to molecules, whether
naturally-occurring or artificially created (e.g., via chemical
synthesis) that have a relatively low molecular weight. Typically,
a small molecule is an organic compound (i.e., it contains carbon).
The small molecule may contain multiple carbon-carbon bonds,
stereocenters, and other functional groups (e.g., amines, hydroxyl,
carbonyls, and heterocyclic rings, etc.). In certain embodiments,
the molecular weight of a small molecule is at most about 1,000
g/mol, at most about 900 g/mol, at most about 800 g/mol, at most
about 700 g/mol, at most about 600 g/mol, at most about 500 g/mol,
at most about 400 g/mol, at most about 300 g/mol, at most about 200
g/mol, or at most about 100 g/mol. In certain embodiments, the
molecular weight of a small molecule is at least 100 g/mol, at
least 200 g/mol, at least 300 g/mol, at least 400 g/mol, at least
500 g/mol, at least 600 g/mol, at least 700 g/mol, at least 800
g/mol, or at least 900 g/mol, or at least 1,000 g/mol. Combinations
of the above ranges (e.g., at least 200 g/mol and at most about 500
g/mol) are also possible. In certain embodiments, the small
molecule is a therapeutically active agent such as a drug (e.g., a
molecule approved by the U.S. Food and Drug Administration as
provided in the Code of Federal Regulations (C.F.R.)). The small
molecule may also be complexed with one or more metal atoms and/or
metal ions. In this instance, the small molecule is also referred
to as a "small organometallic molecule." Preferred small molecules
are biologically active in that they produce a biological effect in
animals, preferably mammals, more preferably humans. Small
molecules include, but are not limited to, radionuclides and
imaging agents. In certain embodiments, the small molecule is a
drug. Preferably, though not necessarily, the drug is one that has
already been deemed safe and effective for use in humans or animals
by the appropriate governmental agency or regulatory body. For
example, drugs approved for human use are listed by the FDA under
21 C.F.R. .sctn..sctn.330.5, 331 through 361, and 440 through 460,
incorporated herein by reference; drugs for veterinary use are
listed by the FDA under 21 C.F.R. .sctn..sctn.500 through 589,
incorporated herein by reference. All listed drugs are considered
acceptable for use in accordance with the present disclosure.
[0105] A "protein," "peptide," or "polypeptide" comprises a polymer
of amino acid residues linked together by peptide bonds. The term
refers to proteins, polypeptides, and peptides of any size,
structure, or function. Typically, a protein will be at least three
amino acids long. A protein may refer to an individual protein or a
collection of proteins. The proteins preferably contain only
natural amino acids, although non-natural amino acids (i.e.,
compounds that do not occur in nature but that can be incorporated
into a polypeptide chain) and/or amino acid analogs as are known in
the art may alternatively be employed. Also, one or more of the
amino acids in a protein may be modified, for example, by the
addition of a chemical entity such as a carbohydrate group, a
hydroxyl group, a phosphate group, a farnesyl group, an isofarnesyl
group, a fatty acid group, a linker for conjugation or
functionalization, or other modification. A protein may also be a
single molecule or may be a multi-molecular complex. A protein may
be a fragment of a naturally occurring protein or peptide. A
protein may be naturally occurring, recombinant, synthetic, or any
combination of these.
[0106] The term "gene" refers to a nucleic acid fragment that
expresses a specific protein, including regulatory sequences
preceding (5' non-coding sequences) and following (3' non-coding
sequences) the coding sequence. "Native gene" refers to a gene as
found in nature with its own regulatory sequences. "Chimeric gene"
or "chimeric construct" refers to any gene or a construct, not a
native gene, comprising regulatory and coding sequences that are
not found together in nature. Accordingly, a chimeric gene or
chimeric construct may comprise regulatory sequences and coding
sequences that are derived from different sources, or regulatory
sequences and coding sequences derived from the same source, but
arranged in a manner different than that found in nature.
"Endogenous gene" refers to a native gene in its natural location
in the genome of an organism. A "foreign" gene refers to a gene not
normally found in the host organism, but which is introduced into
the host organism by gene transfer. Foreign genes can comprise
native genes inserted into a non-native organism, or chimeric
genes. A "transgene" is a gene that has been introduced into the
genome by a transformation procedure.
[0107] The terms "polynucleotide", "nucleotide sequence", "nucleic
acid", "nucleic acid molecule", "nucleic acid sequence", and
"oligonucleotide" refer to a series of nucleotide bases (also
called "nucleotides") in DNA and RNA, and mean any chain of two or
more nucleotides. The polynucleotides can be chimeric mixtures or
derivatives or modified versions thereof, single-stranded or
double-stranded. The oligonucleotide can be modified at the base
moiety, sugar moiety, or phosphate backbone, for example, to
improve stability of the molecule, its hybridization parameters,
etc. The antisense oligonuculeotide may comprise a modified base
moiety which is selected from the group including, but not limited
to, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil,
hypoxanthine, xanthine, 4-acetylcytosine, 5-(carboxyhydroxylmethyl)
uracil, 5-carboxymethylaminomethyl-2-thiouridine,
5-carboxymethylaminomethyluracil, dihydrouracil,
beta-D-galactosylqueosine, inosine, N6-isopentenyladenine,
1-methylguanine, 1-methylinosine, 2,2-dimethylguanine,
2-methyladenine, 2-methylguanine, 3-methylcytosine,
5-methylcytosine, N6-adenine, 7-methylguanine,
5-methylaminomethyluracil, 5-methoxyaminomethyl-2-thiouracil,
beta-D-mannosylqueosine, 5'-methoxycarboxymethyluracil,
5-methoxyuracil, 2-methylthio-N6-isopentenyladenine, wybutoxosine,
pseudouracil, queosine, 2-thiocytosine, 5-methyl-2-thiouracil,
2-thiouracil, 4-thiouracil, 5-methyluracil, uracil-5-oxyacetic acid
methylester, uracil-5-oxyacetic acid, 5-methyl-2-thiouracil,
3-(3-amino-3-N-2-carboxypropyl) uracil, a thio-guanine, and
2,6-diaminopurine. A nucleotide sequence typically carries genetic
information, including the information used by cellular machinery
to make proteins and enzymes. These terms include double- or
single-stranded genomic and cDNA, RNA, any synthetic and
genetically manipulated polynucleotide, and both sense and
antisense polynucleotides. This includes single- and
double-stranded molecules, i.e., DNA-DNA, DNA-RNA and RNA-RNA
hybrids, as well as "protein nucleic acids" (PNAs) formed by
conjugating bases to an amino acid backbone. This also includes
nucleic acids containing carbohydrate or lipids. Exemplary DNAs
include single-stranded DNA (ssDNA), double-stranded DNA (dsDNA),
plasmid DNA (pDNA), genomic DNA (gDNA), complementary DNA (cDNA),
antisense DNA, chloroplast DNA (ctDNA or cpDNA), microsatellite
DNA, mitochondrial DNA (mtDNA or mDNA), kinetoplast DNA (kDNA),
provirus, lysogen, repetitive DNA, satellite DNA, and viral DNA.
Exemplary RNAs include single-stranded RNA (ssRNA), double-stranded
RNA (dsRNA), small interfering RNA (siRNA), messenger RNA (mRNA),
precursor messenger RNA (pre-mRNA), small hairpin RNA or short
hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), transfer
RNA (tRNA), antisense RNA (asRNA), heterogeneous nuclear RNA
(hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA
(long ncRNA or lncRNA), satellite RNA, viral satellite RNA, signal
recognition particle RNA, small cytoplasmic RNA, small nuclear RNA
(snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA),
polyinosinic acid, ribozyme, flexizyme, small nucleolar RNA
(snoRNA), spliced leader RNA, viral RNA, and viral satellite
RNA.
[0108] Polynucleotides described herein may be synthesized by
standard methods known in the art, e.g., by use of an automated DNA
synthesizer (such as those that are commercially available from
Biosearch, Applied Biosystems, etc.). As examples, phosphorothioate
oligonucleotides may be synthesized by the method of Stein et al.,
Nucl. Acids Res., 16, 3209, (1988), methylphosphonate
oligonucleotides can be prepared by use of controlled pore glass
polymer supports (Sarin et al., Proc. Natl. Acad. Sci. U.S.A. 85,
7448-7451, (1988)). A number of methods have been developed for
delivering antisense DNA or RNA to cells, e.g., antisense molecules
can be injected directly into the tissue site, or modified
antisense molecules, designed to target the desired cells
(antisense linked to peptides or antibodies that specifically bind
receptors or antigens expressed on the target cell surface) can be
administered systemically. Alternatively, RNA molecules may be
generated by in vitro and in vivo transcription of DNA sequences
encoding the antisense RNA molecule. Such DNA sequences may be
incorporated into a wide variety of vectors that incorporate
suitable RNA polymerase promoters such as the T7 or SP6 polymerase
promoters. Alternatively, antisense cDNA constructs that synthesize
antisense RNA constitutively or inducibly, depending on the
promoter used, can be introduced stably into cell lines. However,
it is often difficult to achieve intracellular concentrations of
the antisense sufficient to suppress translation of endogenous
mRNAs. Therefore a preferred approach utilizes a recombinant DNA
construct in which the antisense oligonucleotide is placed under
the control of a strong promoter. The use of such a construct to
transfect target cells in the subject will result in the
transcription of sufficient amounts of single stranded RNAs that
will form complementary base pairs with the endogenous target gene
transcripts and thereby prevent translation of the target gene
mRNA. For example, a vector can be introduced in vivo such that it
is taken up by a cell and directs the transcription of an antisense
RNA. Such a vector can remain episomal or become chromosomally
integrated, as long as it can be transcribed to produce the desired
antisense RNA. Such vectors can be constructed by recombinant DNA
technology methods standard in the art. Vectors can be plasmid,
viral, or others known in the art, used for replication and
expression in mammalian cells. Expression of the sequence encoding
the antisense RNA can be by any promoter known in the art to act in
mammalian, preferably human, cells. Such promoters can be inducible
or constitutive. Such promoters include, but are not limited to:
the SV40 early promoter region (Bernoist et al., Nature, 290,
304-310, (1981); Yamamoto et al., Cell, 22, 787-797, (1980); Wagner
et al., Proc. Natl. Acad. Sci. U.S.A. 78, 1441-1445, (1981);
Brinster et al., Nature 296, 39-42, (1982)). Any type of plasmid,
cosmid, yeast artificial chromosome, or viral vector can be used to
prepare the recombinant DNA construct that can be introduced
directly into the tissue site. Alternatively, viral vectors can be
used which selectively infect the desired tissue, in which case
administration may be accomplished by another route (e.g.,
systemically).
[0109] The polynucleotides may be flanked by natural regulatory
(expression control) sequences or may be associated with
heterologous sequences, including promoters, internal ribosome
entry sites (IRES) and other ribosome binding site sequences,
enhancers, response elements, suppressors, signal sequences,
polyadenylation sequences, introns, 5'- and 3'-non-coding regions,
and the like. The nucleic acids may also be modified by many means
known in the art. Non-limiting examples of such modifications
include methylation, "caps", substitution of one or more of the
naturally occurring nucleotides with an analog, and internucleotide
modifications, such as, for example, those with uncharged linkages
(e.g., methyl phosphonates, phosphotriesters, phosphoroamidates,
carbamates, etc.) and with charged linkages (e.g.,
phosphorothioates, phosphorodithioates, etc.). Polynucleotides may
contain one or more additional covalently linked moieties, such as,
for example, proteins (e.g., nucleases, toxins, antibodies, signal
peptides, poly-L-lysine, etc.), intercalators (e.g., acridine,
psoralen, etc.), chelators (e.g., metals, radioactive metals, iron,
oxidative metals, etc.), and alkylators. The polynucleotides may be
derivatized by formation of a methyl or ethyl phosphotriester or an
alkyl phosphoramidate linkage. Furthermore, the polynucleotides
herein may also be modified with a label capable of providing a
detectable signal, either directly or indirectly. Exemplary labels
include radioisotopes, fluorescent molecules, isotopes (e.g.,
radioactive isotopes), biotin, and the like.
[0110] A "recombinant nucleic acid molecule" is a nucleic acid
molecule that has undergone a molecular biological manipulation,
i.e., non-naturally occurring nucleic acid molecule or genetically
engineered nucleic acid molecule. Furthermore, the term
"recombinant DNA molecule" refers to a nucleic acid sequence which
is not naturally occurring, or can be made by the artificial
combination of two otherwise separated segments of nucleic acid
sequence, i.e., by ligating together pieces of DNA that are not
normally continuous. By "recombinantly produced" is meant
artificial combination often accomplished by either chemical
synthesis means, or by the artificial manipulation of isolated
segments of nucleic acids, e.g., by genetic engineering techniques
using restriction enzymes, ligases, and similar recombinant
techniques as described by, for example, Sambrook et al., Molecular
Cloning, second edition, Cold Spring Harbor Laboratory, Plainview,
N.Y.; (1989), or Ausubel et al., Current Protocols in Molecular
Biology, Current Protocols (1989), and DNA Cloning: A Practical
Approach, Volumes I and II (ed. D. N. Glover) IREL Press, Oxford,
(1985); each of which is incorporated herein by reference.
[0111] Such manipulation may be done to replace a codon with a
redundant codon encoding the same or a conservative amino acid,
while typically introducing or removing a sequence recognition
site. Alternatively, it may be performed to join together nucleic
acid segments of desired functions to generate a single genetic
entity comprising a desired combination of functions not found in
nature. Restriction enzyme recognition sites are often the target
of such artificial manipulations, but other site specific targets,
e.g., promoters, DNA replication sites, regulation sequences,
control sequences, open reading frames, or other useful features
may be incorporated by design.
[0112] The term "pDNA," "plasmid DNA," or "plasmid" refers to a
small DNA molecule that is physically separate from, and can
replicate independently of, chromosomal DNA within a cell. Plasmids
can be found in all three major domains: Archaea, Bacteria, and
Eukarya. In nature, plasmids carry genes that may benefit survival
of the subject (e.g., antibiotic resistance) and can frequently be
transmitted from one bacterium to another (even of another species)
via horizontal gene transfer. Artificial plasmids are widely used
as vectors in molecular cloning, serving to drive the replication
of recombinant DNA sequences within host subjects. Plasmid sizes
may vary from 1 to over 1,000 kbp. Plasmids are considered
replicons, capable of replicating autonomously within a suitable
host.
[0113] "RNA transcript" refers to the product resulting from RNA
polymerase-catalyzed transcription of a DNA sequence. When the RNA
transcript is a complementary copy of the DNA sequence, it is
referred to as the primary transcript, or it may be an RNA sequence
derived from post-transcriptional processing of the primary
transcript and is referred to as the mature RNA. "Messenger RNA
(mRNA)" refers to the RNA that is without introns and can be
translated into polypeptides by the cell. "cRNA" refers to
complementary RNA, transcribed from a recombinant cDNA template.
"cDNA" refers to DNA that is complementary to and derived from an
mRNA template. The cDNA can be single-stranded or converted to
double-stranded form using, for example, the Klenow fragment of DNA
polymerase I.
[0114] A sequence "complementary" to a portion of an RNA, refers to
a sequence having sufficient complementarity to be able to
hybridize with the RNA, forming a stable duplex; in the case of
double-stranded antisense nucleic acids, a single strand of the
duplex DNA may thus be tested, or triplex formation may be assayed.
The ability to hybridize will depend on both the degree of
complementarity and the length of the antisense nucleic acid.
Generally, the longer the hybridizing nucleic acid, the more base
mismatches with an RNA it may contain and still form a stable
duplex (or triplex, as the case may be). One skilled in the art can
ascertain a tolerable degree of mismatch by use of standard
procedures to determine the melting point of the hybridized
complex.
[0115] The terms "nucleic acid" or "nucleic acid sequence",
"nucleic acid molecule", "nucleic acid fragment" or
"polynucleotide" may be used interchangeably with "gene", "mRNA
encoded by a gene" and "cDNA".
[0116] The term "mRNA" or "mRNA molecule" refers to messenger RNA,
or the RNA that serves as a template for protein synthesis in a
cell. The sequence of a strand of mRNA is based on the sequence of
a complementary strand of DNA comprising a sequence coding for the
protein to be synthesized.
[0117] The term "siRNA" or "siRNA molecule" refers to small
inhibitory RNA duplexes that induce the RNA interference (RNAi)
pathway, where the siRNA interferes with the expression of specific
genes with a complementary nucleotide sequence. siRNA molecules can
vary in length (e.g., between 18-30 or 20-25 basepairs) and contain
varying degrees of complementarity to their target mRNA in the
antisense strand. Some siRNA have unpaired overhanging bases on the
5' or 3' end of the sense strand and/or the antisense strand. The
term siRNA includes duplexes of two separate strands, as well as
single strands that can form hairpin structures comprising a duplex
region.
[0118] The term "gene silencing" refers to an epigenetic process of
gene regulation where a gene is "switched off" by a mechanism other
than genetic modification. That is, a gene which would be expressed
(i.e., "turned on") under normal circumstances is switched off by
machinery in the cell. Gene silencing occurs when RNA is unable to
make a protein during translation. Genes are regulated at either
the transcriptional or post-transcriptional level. Transcriptional
gene silencing is the result of histone modifications, creating an
environment of heterochromatin around a gene that makes it
inaccessible to transcriptional machinery (e.g., RNA polymerase and
transcription factors). Post-transcriptional gene silencing is the
result of mRNA of a particular gene being destroyed or blocked. The
destruction of the mRNA prevents translation and thus the formation
of a gene product (e.g., a protein). A common mechanism of
post-transcriptional gene silencing is RNAi.
[0119] The term "cage" refers to a sphere or paddlewheel.
[0120] The term "sphere" or "spherical" refers to a cage-like
structure, which is hollow and has at least one reflectional
symmetry, rotational symmetry, or a combination thereof. The term
"nanosphere" refers to a sphere, wherein the maximum outer
dimension (e.g., diameter) of the sphere is between 1 nanometer
(nm) and about 1 micrometer (.mu.m) (e.g., between about 1 nm and
about 300 nm, between about 1 nm and about 100 nm, between about 1
nm and about 30 nm, between about 1 nm and about 10 nm, or between
about 1 nm and about 3 nm), inclusive).
[0121] The term "paddlewheel" or "paddle wheel" refers to a
coordination complex comprising m instances of ligands and two
metal centers (metal atoms or metal ions), wherein there is an axis
of symmetry connecting the two metal centers, and the overall
symmetry of the coordination complex falls into the Dmh point
group. In certain embodiments, m is 4, and the point group is D4h
(e.g., there is a four-fold axis of symmetry when looking down the
metal centers). In certain embodiments, the geometry of each of the
metal centers is substantially square planar. In certain
embodiments, m is 3. The term "nano-paddlewheel" refers to a
paddlewheel, wherein the maximum outer dimension (e.g., diameter)
of the paddlewheel is between 1 nanometer (nm) and about 1
micrometer (.mu.m) (e.g., between about 1 nm and about 300 nm,
between about 1 nm and about 100 nm, between about 1 nm and about
30 nm, between about 1 nm and about 10 nm, or between about 1 nm
and about 3 nm), inclusive). In certain embodiments, a
nano-paddlewheel described herein is of the formula depicted in
FIG. 42.
[0122] The term "particle" refers to a small object, fragment, or
piece of a substance that may be a single element, inorganic
material, organic material, or mixture thereof. Examples of
particles include polymeric particles, single-emulsion particles,
double-emulsion particles, coacervates, liposomes, microparticles,
nanoparticles, macroscopic particles, pellets, crystals,
aggregates, composites, pulverized, milled or otherwise disrupted
matrices, and cross-linked protein or polysaccharide particles,
each of which have an average (e.g., mean) characteristic dimension
of about not more than 1 mm and at least 1 nm, where the
characteristic dimension, or "critical dimension," of the particle
is the smallest cross-sectional dimension of the particle. A
particle may be composed of a single substance or multiple
substances. In certain embodiments, the particle is not a viral
particle. In other embodiments, the particle is not a liposome. In
certain embodiments, the particle is not a micelle. In certain
embodiments, the particle is substantially solid throughout. In
certain embodiments, the particle is a nanoparticle. In certain
embodiments, the particle is a microparticle.
[0123] The term "nanoparticle" refers to a particle having an
average (e.g., mean) dimension (e.g., diameter) of between about 1
nanometer (nm) and about 1 micrometer (.mu.m) (e.g., between about
1 nm and about 300 nm, between about 1 nm and about 100 nm, between
about 1 nm and about 30 nm, between about 1 nm and about 10 nm, or
between about 1 nm and about 3 nm), inclusive.
[0124] The term "microparticle" refers to a particle having an
average (e.g., mean) dimension (e.g., diameter) of between about 1
micrometer (.mu.m) and about 1 millimeter (mm) (e.g., between about
1 .mu.m and about 100 .mu.m, between about 1 .mu.m and about 30
.mu.m, between about 1 .mu.m and about 10 .mu.m, or between about 1
.mu.m and about 3 .mu.m), inclusive.
[0125] The term "fluid" refers to a substance that, under a shear
stress at 25.degree. C., continually flows (e.g., at a velocity of
1 millimeter per second) along a solid boundary. Examples of fluids
include liquids (e.g., solvents and solutions), gases, and
suspensions (where solids are suspended in a liquid or gas). In
certain embodiments, a fluid is water. In certain embodiments, a
fluid is DMSO or acetonitrile. In certain embodiments, a fluid is
water, DMSO, acetonide, or a mixture thereof. A "nonfluid" is a
substance that is not a fluid.
[0126] The term "gel" is a nonfluid colloidal network or nonfluid
polymer network that is expanded throughout its whole volume by a
fluid (e.g., a solvent (e.g., water) or a solution (e.g., an
aqueous solution)). A gel has a finite, usually rather small, yield
stress. A gel may contain: (i) a covalent molecular network (e.g.,
polymer network), e.g., a network formed by crosslinking molecules
(e.g., polymers) or by nonlinear polymerization; (ii) a molecular
network (e.g., polymer network) formed through non-covalent
aggregation of molecules (e.g., polymers), caused by complexation
(e.g., coordination bond formation between a ligand and a metal,
the resulting gel referring to a "metallogel"), electrostatic
interactions, hydrophobic interactions, hydrogen bonding, van der
Waals interactions, .pi.-.pi. stacking, or a combination thereof,
that results in regions of local order acting as the network
junction points. The term "thermoreversible gel" refers to a gel
where the regions of local order in the gel are thermally
reversible; (iii) a polymer network formed through glassy junction
points, e.g., one based on block copolymers. If the junction points
are thermally reversible glassy domains, the resulting swollen
network may also be termed a thermoreversible gel; (iv) lamellar
structures including mesophases, e.g., soap gels, phospholipids,
and clays; or (v) particulate disordered structures, e.g., a
flocculent precipitate usually consisting of particles with large
geometrical anisotropy, such as in V.sub.2O.sub.5 gels and globular
or fibrillar protein gels. The term "hydrogel" refers to a gel, in
which the fluid is water.
The term "interstructural" refers to a divalent linker Y directly
covalently attached to two different instances of a metal organic
nanostructure. The term "intrastructural" refers to a divalent
linker Y directly covalently attached to the same instance of a
metal organic nanostructure.
[0127] The terms "composition" and "formulation" are used
interchangeably.
[0128] A "subject" to which administration is contemplated refers
to a human (i.e., male or female of any age group, e.g., pediatric
subject (e.g., infant, child, or adolescent) or adult subject
(e.g., young adult, middle-aged adult, or senior adult)) or
non-human animal. In certain embodiments, the non-human animal is a
mammal (e.g., primate (e.g., cynomolgus monkey or rhesus monkey),
commercially relevant mammal (e.g., cattle, pig, horse, sheep,
goat, cat, or dog), or bird (e.g., commercially relevant bird, such
as chicken, duck, goose, or turkey)). In certain embodiments, the
non-human animal is a fish, reptile, or amphibian. The non-human
animal may be a male or female at any stage of development. The
non-human animal may be a transgenic animal or genetically
engineered animal.
[0129] The term "target tissue" refers to any biological tissue of
a subject (including a group of cells, a body part, or an organ) or
a part thereof, including blood and/or lymph vessels, which is the
object to which a compound, particle, and/or composition of the
disclosure is delivered. A target tissue may be an abnormal or
unhealthy tissue, which may need to be treated. A target tissue may
also be a normal or healthy tissue that is under a higher than
normal risk of becoming abnormal or unhealthy, which may need to be
prevented. In certain embodiments, the target tissue is the liver.
In certain embodiments, the target tissue is the lung. In certain
embodiments, the target tissue is the spleen. A "non-target tissue"
is any biological tissue of a subject (including a group of cells,
a body part, or an organ) or a part thereof, including blood and/or
lymph vessels, which is not a target tissue.
[0130] The terms "administer," "administering," or "administration"
refers to implanting, absorbing, ingesting, injecting, inhaling, or
otherwise introducing a compound described herein, or a composition
thereof, in or on a subject.
[0131] The terms "treatment," "treat," and "treating" refer to
reversing, alleviating, delaying the onset of, or inhibiting the
progress of a disease described herein. In some embodiments,
treatment may be administered after one or more signs or symptoms
of the disease have developed or have been observed. In other
embodiments, treatment may be administered in the absence of signs
or symptoms of the disease. For example, treatment may be
administered to a susceptible subject prior to the onset of
symptoms (e.g., in light of a history of symptoms and/or in light
of exposure to a pathogen). Treatment may also be continued after
symptoms have resolved, for example, to delay or prevent
recurrence.
[0132] The term "prevent," "preventing," or "prevention" refers to
a prophylactic treatment of a subject who is not and was not with a
disease but is at risk of developing the disease or who was with a
disease, is not with the disease, but is at risk of regression of
the disease. In certain embodiments, the subject is at a higher
risk of developing the disease or at a higher risk of regression of
the disease than an average healthy member of a population of
subjects.
[0133] The terms "condition," "disease," and "disorder" are used
interchangeably.
[0134] An "effective amount" of a compound described herein refers
to an amount sufficient to elicit the desired biological response,
i.e., treating the condition. As will be appreciated by those of
ordinary skill in this art, the effective amount of a compound
described herein may vary depending on such factors as the desired
biological endpoint, the pharmacokinetics of the compound, the
condition being treated, the mode of administration, and the age
and health of the subject. An effective amount encompasses
therapeutic and prophylactic treatment.
[0135] A "therapeutically effective amount" of a compound described
herein is an amount sufficient to provide a therapeutic benefit in
the treatment of a condition or to delay or minimize one or more
symptoms associated with the condition. A therapeutically effective
amount of a compound means an amount of therapeutic agent, alone or
in combination with other therapies, which provides a therapeutic
benefit in the treatment of the condition. The term
"therapeutically effective amount" can encompass an amount that
improves overall therapy, reduces or avoids symptoms, signs, or
causes of the condition, and/or enhances the therapeutic efficacy
of another therapeutic agent.
[0136] A "prophylactically effective amount" of a compound
described herein is an amount sufficient to prevent a condition, or
one or more symptoms associated with the condition or prevent its
recurrence. A prophylactically effective amount of a compound means
an amount of a therapeutic agent, alone or in combination with
other agents, which provides a prophylactic benefit in the
prevention of the condition. The term "prophylactically effective
amount" can encompass an amount that improves overall prophylaxis
or enhances the prophylactic efficacy of another prophylactic
agent.
[0137] The term "genetic disease" refers to a disease caused by one
or more abnormalities in the genome of a subject, such as a disease
that is present from birth of the subject. Genetic diseases may be
heritable and may be passed down from the parents' genes. A genetic
disease may also be caused by mutations or changes of the DNAs
and/or RNAs of the subject. In such cases, the genetic disease will
be heritable if it occurs in the germline. Exemplary genetic
diseases include, but are not limited to, Aarskog-Scott syndrome,
Aase syndrome, achondroplasia, acrodysostosis, addiction,
adreno-leukodystrophy, albinism, ablepharon-macrostomia syndrome,
alagille syndrome, alkaptonuria, alpha-1 antitrypsin deficiency,
Alport's syndrome, Alzheimer's disease, asthma, autoimmune
polyglandular syndrome, androgen insensitivity syndrome, Angelman
syndrome, ataxia, ataxia telangiectasia, atherosclerosis, attention
deficit hyperactivity disorder (ADHD), autism, baldness, Batten
disease, Beckwith-Wiedemann syndrome, Best disease, bipolar
disorder, brachydactyl), breast cancer, Burkitt lymphoma, chronic
myeloid leukemia, Charcot-Marie-Tooth disease, Crohn's disease,
cleft lip, Cockayne syndrome, Coffin Lowry syndrome, colon cancer,
congenital adrenal hyperplasia, Cornelia de Lange syndrome,
Costello syndrome, Cowden syndrome, craniofrontonasal dysplasia,
Crigler-Najjar syndrome, Creutzfeldt-Jakob disease, cystic
fibrosis, deafness, depression, diabetes, diastrophic dysplasia,
DiGeorge syndrome, Down's syndrome, dyslexia, Duchenne muscular
dystrophy, Dubowitz syndrome, ectodermal dysplasia Ellis-van
Creveld syndrome, Ehlers-Danlos, epidermolysis bullosa, epilepsy,
essential tremor, familial hypercholesterolemia, familial
Mediterranean fever, fragile X syndrome, Friedreich's ataxia,
Gaucher disease, glaucoma, glucose galactose malabsorption,
glutaricaciduria, gyrate atrophy, Goldberg Shprintzen syndrome
(velocardiofacial syndrome), Gorlin syndrome, Hailey-Hailey
disease, hemihypertrophy, hemochromatosis, hemophilia, hereditary
motor and sensory neuropathy (HMSN), hereditary non polyposis
colorectal cancer (HNPCC), Huntington's disease, immunodeficiency
with hyper-IgM, juvenile onset diabetes, Klinefelter's syndrome,
Kabuki syndrome, Leigh's disease, long QT syndrome, lung cancer,
malignant melanoma, manic depression, Marfan syndrome, Menkes
syndrome, miscarriage, mucopolysaccharide disease, multiple
endocrine neoplasia, multiple sclerosis, muscular dystrophy,
myotrophic lateral sclerosis, myotonic dystrophy,
neurofibromatosis, Niemann-Pick disease, Noonan syndrome, obesity,
ovarian cancer, pancreatic cancer, Parkinson's disease, paroxysmal
nocturnal hemoglobinuria, Pendred syndrome, peroneal muscular
atrophy, phenylketonuria (PKU), polycystic kidney disease,
Prader-Willi syndrome, primary biliary cirrhosis, prostate cancer,
REAR syndrome, Refsum disease, retinitis pigmentosa,
retinoblastoma, Rett syndrome, Sanfilippo syndrome, schizophrenia,
severe combined immunodeficiency, sickle cell anemia, spina bifida,
spinal muscular atrophy, spinocerebellar atrophy, sudden adult
death syndrome, Tangier disease, Tay-Sachs disease,
thrombocytopenia absent radius syndrome, Townes-Brocks syndrome,
tuberous sclerosis, Turner syndrome, Usher syndrome, von
Hippel-Lindau syndrome, Waardenburg syndrome, Weaver syndrome,
Werner syndrome, Williams syndrome, Wilson's disease, xeroderma
piginentosum, and Zellweger syndrome.
[0138] A "proliferative disease" refers to a disease that occurs
due to abnormal growth or extension by the multiplication of cells
(Walker, Cambridge Dictionary of Biology; Cambridge University
Press: Cambridge, UK, 1990). A proliferative disease may be
associated with: 1) the pathological proliferation of normally
quiescent cells; 2) the pathological migration of cells from their
normal location (e.g., metastasis of neoplastic cells); 3) the
pathological expression of proteolytic enzymes such as the matrix
metalloproteinases (e.g., collagenases, gelatinases, and
elastases); or 4) the pathological angiogenesis as in proliferative
retinopathy and tumor metastasis. Exemplary proliferative diseases
include cancers (i.e., "malignant neoplasms"), benign neoplasms,
angiogenesis, inflammatory diseases, and autoimmune diseases.
[0139] The term "angiogenesis" refers to the physiological process
through which new blood vessels form from pre-existing vessels.
Angiogenesis is distinct from vasculogenesis, which is the de novo
formation of endothelial cells from mesoderm cell precursors. The
first vessels in a developing embryo form through vasculogenesis,
after which angiogenesis is responsible for most blood vessel
growth during normal or abnormal development. Angiogenesis is a
vital process in growth and development, as well as in wound
healing and in the formation of granulation tissue. However,
angiogenesis is also a fundamental step in the transition of tumors
from a benign state to a malignant one, leading to the use of
angiogenesis inhibitors in the treatment of cancer. Angiogenesis
may be chemically stimulated by angiogenic proteins, such as growth
factors (e.g., VEGF). "Pathological angiogenesis" refers to
abnormal (e.g., excessive or insufficient) angiogenesis that
amounts to and/or is associated with a disease.
[0140] The terms "neoplasm" and "tumor" are used interchangeably
and refer to an abnormal mass of tissue wherein the growth of the
mass surpasses and is not coordinated with the growth of a normal
tissue. A neoplasm or tumor may be "benign" or "malignant,"
depending on the following characteristics: degree of cellular
differentiation (including morphology and functionality), rate of
growth, local invasion, and metastasis. A "benign neoplasm" is
generally well differentiated, has characteristically slower growth
than a malignant neoplasm, and remains localized to the site of
origin. In addition, a benign neoplasm does not have the capacity
to infiltrate, invade, or metastasize to distant sites. Exemplary
benign neoplasms include, but are not limited to, lipoma,
chondroma, adenomas, acrochordon, senile angiomas, seborrheic
keratoses, lentigos, and sebaceous hyperplasias. In some cases,
certain "benign" tumors may later give rise to malignant neoplasms,
which may result from additional genetic changes in a subpopulation
of the tumor's neoplastic cells, and these tumors are referred to
as "pre-malignant neoplasms." An exemplary pre-malignant neoplasm
is a teratoma. In contrast, a "malignant neoplasm" is generally
poorly differentiated (anaplasia) and has characteristically rapid
growth accompanied by progressive infiltration, invasion, and
destruction of the surrounding tissue. Furthermore, a malignant
neoplasm generally has the capacity to metastasize to distant
sites. The term "metastasis," "metastatic," or "metastasize" refers
to the spread or migration of cancerous cells from a primary or
original tumor to another organ or tissue and is typically
identifiable by the presence of a "secondary tumor" or "secondary
cell mass" of the tissue type of the primary or original tumor and
not of that of the organ or tissue in which the secondary
(metastatic) tumor is located. For example, a prostate cancer that
has migrated to bone is said to be metastasized prostate cancer and
includes cancerous prostate cancer cells growing in bone
tissue.
[0141] The term "cancer" refers to a malignant neoplasm (Stedman's
Medical Dictionary, 25th ed.; Hensyl ed.; Williams & Wilkins:
Philadelphia, 1990). Exemplary cancers include, but are not limited
to, acoustic neuroma; adenocarcinoma; adrenal gland cancer; anal
cancer; angiosarcoma (e.g., lymphangiosarcoma,
lymphangioendotheliosarcoma, hemangiosarcoma); appendix cancer;
benign monoclonal gammopathy; biliary cancer (e.g.,
cholangiocarcinoma); bladder cancer; breast cancer (e.g.,
adenocarcinoma of the breast, papillary carcinoma of the breast,
mammary cancer, medullary carcinoma of the breast); brain cancer
(e.g., meningioma, glioblastomas, glioma (e.g., astrocytoma,
oligodendroglioma), medulloblastoma); bronchus cancer; carcinoid
tumor; cervical cancer (e.g., cervical adenocarcinoma);
choriocarcinoma; chordoma; craniopharyngioma; colorectal cancer
(e.g., colon cancer, rectal cancer, colorectal adenocarcinoma);
connective tissue cancer; epithelial carcinoma; ependymoma;
endotheliosarcoma (e.g., Kaposi's sarcoma, multiple idiopathic
hemorrhagic sarcoma); endometrial cancer (e.g., uterine cancer,
uterine sarcoma); esophageal cancer (e.g., adenocarcinoma of the
esophagus, Barrett's adenocarcinoma); Ewing's sarcoma; ocular
cancer (e.g., intraocular melanoma, retinoblastoma); familiar
hypereosinophilia; gall bladder cancer; gastric cancer (e.g.,
stomach adenocarcinoma); gastrointestinal stromal tumor (GIST);
germ cell cancer; head and neck cancer (e.g., head and neck
squamous cell carcinoma, oral cancer (e.g., oral squamous cell
carcinoma), throat cancer (e.g., laryngeal cancer, pharyngeal
cancer, nasopharyngeal cancer, oropharyngeal cancer));
hematopoietic cancers (e.g., leukemia such as acute lymphocytic
leukemia (ALL) (e.g., B-cell ALL, T-cell ALL), acute myelocytic
leukemia (AML) (e.g., B-cell AML, T-cell AML), chronic myelocytic
leukemia (CML) (e.g., B-cell CML, T-cell CML), and chronic
lymphocytic leukemia (CLL) (e.g., B-cell CLL, T-cell CLL));
lymphoma such as Hodgkin lymphoma (HL) (e.g., B-cell HL, T-cell HL)
and non-Hodgkin lymphoma (NHL) (e.g., B-cell NHL such as diffuse
large cell lymphoma (DLCL) (e.g., diffuse large B-cell lymphoma),
follicular lymphoma, chronic lymphocytic leukemia/small lymphocytic
lymphoma (CLL/SLL), mantle cell lymphoma (MCL), marginal zone
B-cell lymphomas (e.g., mucosa-associated lymphoid tissue (MALT)
lymphomas, nodal marginal zone B-cell lymphoma, splenic marginal
zone B-cell lymphoma), primary mediastinal B-cell lymphoma, Burkitt
lymphoma, lymphoplasmacytic lymphoma (i.e., Waldenstrim's
macroglobulinemia), hairy cell leukemia (HCL), immunoblastic large
cell lymphoma, precursor B-lymphoblastic lymphoma and primary
central nervous system (CNS) lymphoma; and T-cell NHL such as
precursor T-lymphoblastic lymphomalleukemia, peripheral T-cell
lymphoma (PTCL) (e.g., cutaneous T-cell lymphoma (CTCL) (e.g.,
mycosis fungiodes, Sezary syndrome), angioimmunoblastic T-cell
lymphoma, extranodal natural killer T-cell lymphoma, enteropathy
type T-cell lymphoma, subcutaneous panniculitis-like T-cell
lymphoma, and anaplastic large cell lymphoma); a mixture of one or
more leukemiallymphoma as described above; and multiple myeloma
(MM)), heavy chain disease (e.g., alpha chain disease, gamma chain
disease, mu chain disease); hemangioblastoma; hypopharynx cancer;
inflammatory myofibroblastic tumors; immunocytic amyloidosis;
kidney cancer (e.g., nephroblastoma a.k.a. Wilms' tumor, renal cell
carcinoma); liver cancer (e.g., hepatocellular cancer (HCC),
malignant hepatoma); lung cancer (e.g., bronchogenic carcinoma,
small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC),
adenocarcinoma of the lung); leiomyosarcoma (LMS); mastocytosis
(e.g., systemic mastocytosis); muscle cancer; myelodysplastic
syndrome (MDS); mesothelioma; myeloproliferative disorder (MPD)
(e.g., polycythemia vera (PV), essential thrombocytosis (ET),
agnogenic myeloid metaplasia (AMM) a.k.a. myelofibrosis (MF),
chronic idiopathic myelofibrosis, chronic myelocytic leukemia
(CML), chronic neutrophilic leukemia (CNL), hypereosinophilic
syndrome (HES)); neuroblastoma; neurofibroma (e.g.,
neurofibromatosis (NF) type 1 or type 2, schwannomatosis);
neuroendocrine cancer (e.g., gastroenteropancreatic
neuroendocrinetumor (GEP-NET), carcinoid tumor); osteosarcoma
(e.g., bone cancer); ovarian cancer (e.g., cystadenocarcinoma,
ovarian embryonal carcinoma, ovarian adenocarcinoma); papillary
adenocarcinoma; pancreatic cancer (e.g., pancreatic
andenocarcinoma, intraductal papillary mucinous neoplasm (IPMN),
Islet cell tumors); penile cancer (e.g., Paget's disease of the
penis and scrotum); pinealoma; primitive neuroectodermal tumor
(PNT); plasma cell neoplasia; paraneoplastic syndromes;
intraepithelial neoplasms; prostate cancer (e.g., prostate
adenocarcinoma); rectal cancer; rhabdomyosarcoma; salivary gland
cancer; skin cancer (e.g., squamous cell carcinoma (SCC),
keratoacanthoma (KA), melanoma, basal cell carcinoma (BCC)); small
bowel cancer (e.g., appendix cancer); soft tissue sarcoma (e.g.,
malignant fibrous histiocytoma (MFH), liposarcoma, malignant
peripheral nerve sheath tumor (MPNST), chondrosarcoma,
fibrosarcoma, myxosarcoma); sebaceous gland carcinoma; small
intestine cancer; sweat gland carcinoma; synovioma; testicular
cancer (e.g., seminoma, testicular embryonal carcinoma); thyroid
cancer (e.g., papillary carcinoma of the thyroid, papillary thyroid
carcinoma (PTC), medullary thyroid cancer); urethral cancer;
vaginal cancer; and vulvar cancer (e.g., Paget's disease of the
vulva).
[0142] The term "inflammatory disease" refers to a disease caused
by, resulting from, or resulting in inflammation. The term
"inflammatory disease" may also refer to a dysregulated
inflammatory reaction that causes an exaggerated response by
macrophages, granulocytes, and/or T-lymphocytes leading to abnormal
tissue damage and/or cell death. An inflammatory disease can be
either an acute or chronic inflammatory condition and can result
from infections or non-infectious causes. Inflammatory diseases
include, without limitation, atherosclerosis, arteriosclerosis,
autoimmune disorders, multiple sclerosis, systemic lupus
erythematosus, polymyalgia rheumatica (PMR), gouty arthritis,
degenerative arthritis, tendonitis, bursitis, psoriasis, cystic
fibrosis, arthrosteitis, rheumatoid arthritis, inflammatory
arthritis, Sjogren's syndrome, giant cell arteritis, progressive
systemic sclerosis (scleroderma), ankylosing spondylitis,
polymyositis, dermatomyositis, pemphigus, pemphigoid, diabetes
(e.g., Type I), myasthenia gravis, Hashimoto's thyroiditis, Graves'
disease, Goodpasture's disease, mixed connective tissue disease,
sclerosing cholangitis, inflammatory bowel disease, Crohn's
disease, ulcerative colitis, pernicious anemia, inflammatory
dermatoses, usual interstitial pneumonitis (UIP), asbestosis,
silicosis, bronchiectasis, berylliosis, talcosis, pneumoconiosis,
sarcoidosis, desquamative interstitial pneumonia, lymphoid
interstitial pneumonia, giant cell interstitial pneumonia, cellular
interstitial pneumonia, extrinsic allergic alveolitis, Wegener's
granulomatosis and related forms of angiitis (temporal arteritis
and polyarteritis nodosa), inflammatory dermatoses, hepatitis,
delayed-type hypersensitivity reactions (e.g., poison ivy
dermatitis), pneumonia, respiratory tract inflammation, Adult
Respiratory Distress Syndrome (ARDS), encephalitis, immediate
hypersensitivity reactions, asthma, hayfever, allergies, acute
anaphylaxis, rheumatic fever, glomerulonephritis, pyelonephritis,
cellulitis, cystitis, chronic cholecystitis, ischemia (ischemic
injury), reperfusion injury, allograft rejection, host-versus-graft
rejection, appendicitis, arteritis, blepharitis, bronchiolitis,
bronchitis, cervicitis, cholangitis, chorioamnionitis,
conjunctivitis, dacryoadenitis, dermatomyositis, endocarditis,
endometritis, enteritis, enterocolitis, epicondylitis,
epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis,
gingivitis, ileitis, iritis, laryngitis, myelitis, myocarditis,
nephritis, omphalitis, oophoritis, orchitis, osteitis, otitis,
pancreatitis, parotitis, pericarditis, pharyngitis, pleuritis,
phlebitis, pneumonitis, proctitis, prostatitis, rhinitis,
salpingitis, sinusitis, stomatitis, synovitis, testitis,
tonsillitis, urethritis, urocystitis, uveitis, vaginitis,
vasculitis, vulvitis, vulvovaginitis, angitis, chronic bronchitis,
osteomyelitis, optic neuritis, temporal arteritis, transverse
myelitis, necrotizing fasciitis, and necrotizing enterocolitis. An
ocular inflammatory disease includes, but is not limited to,
post-surgical inflammation.
[0143] An "autoimmune disease" refers to a disease arising from an
inappropriate immune response of the body of a subject against
substances and tissues normally present in the body. In other
words, the immune system mistakes some part of the body as a
pathogen and attacks its own cells. This may be restricted to
certain organs (e.g., in autoimmune thyroiditis) or involve a
particular tissue in different places (e.g., Goodpasture's disease
which may affect the basement membrane in both the lung and
kidney). The treatment of autoimmune diseases is typically with
immunosuppression, e.g., medications which decrease the immune
response. Exemplary autoimmune diseases include, but are not
limited to, glomerulonephritis, Goodpasture's syndrome, necrotizing
vasculitis, lymphadenitis, peri-arteritis nodosa, systemic lupus
erythematosis, rheumatoid, arthritis, psoriatic arthritis, systemic
lupus erythematosis, psoriasis, ulcerative colitis, systemic
sclerosis, dermatomyositis/polymyositis, anti-phospholipid antibody
syndrome, scleroderma, pemphigus vulgaris, ANCA-associated
vasculitis (e.g., Wegener's granulomatosis, microscopic
polyangiitis), uveitis, Sjogren's syndrome, Crohn's disease,
Reiter's syndrome, ankylosing spondylitis, Lyme disease,
Guillain-Barre syndrome, Hashimoto's thyroiditis, and
cardiomyopathy.
[0144] The term "liver disease" or "hepatic disease" refers to
damage to or a disease of the liver. Non-limiting examples of liver
disease include intrahepatic cholestasis (e.g., alagille syndrome,
biliary liver cirrhosis), fatty liver (e.g., alcoholic fatty liver,
Reye's syndrome), hepatic vein thrombosis, hepatolenticular
degeneration (i.e., Wilson's disease), hepatomegaly, liver abscess
(e.g., amebic liver abscess), liver cirrhosis (e.g., alcoholic,
biliary, and experimental liver cirrhosis), alcoholic liver
diseases (e.g., fatty liver, hepatitis, cirrhosis), parasitic liver
disease (e.g., hepatic echinococcosis, fascioliasis, amebic liver
abscess), jaundice (e.g., hemolytic, hepatocellular, cholestatic
jaundice), cholestasis, portal hypertension, liver enlargement,
ascites, hepatitis (e.g., alcoholic hepatitis, animal hepatitis,
chronic hepatitis (e.g., autoimmune, hepatitis B, hepatitis C,
hepatitis D, drug induced chronic hepatitis), toxic hepatitis,
viral human hepatitis (e.g., hepatitis A, hepatitis B, hepatitis C,
hepatitis D, hepatitis E), granulomatous hepatitis, secondary
biliary cirrhosis, hepatic encephalopathy, varices, primary biliary
cirrhosis, primary sclerosing cholangitis, hepatocellular adenoma,
hemangiomas, bile stones, liver failure (e.g., hepatic
encephalopathy, acute liver failure), angiomyolipoma, calcified
liver metastases, cystic liver metastases, fibrolamellar
hepatocarcinoma, hepatic adenoma, hepatoma, hepatic cysts (e.g.,
Simple cysts, Polycystic liver disease, hepatobiliary cystadenoma,
choledochal cyst), mesenchymal tumors (mesenchymal hamartoma,
infantile hemangioendothelioma, hemangioma, peliosis hepatis,
lipomas, inflammatory pseudotumor), epithelial tumors (e.g., bile
duct hamartoma, bile duct adenoma), focal nodular hyperplasia,
nodular regenerative hyperplasia, hepatoblastoma, hepatocellular
carcinoma, cholangiocarcinoma, cystadenocarcinoma, tumors of blood
vessels, angiosarcoma, Karposi's sarcoma, hemangioendothelioma,
embryonal sarcoma, fibrosarcoma, leiomyosarcoma, rhabdomyosarcoma,
carcinosarcoma, teratoma, carcinoid, squamous carcinoma, primary
lymphoma, peliosis hepatis, erythrohepatic porphyria, hepatic
porphyria (e.g., acute intermittent porphyria, porphyria cutanea
tarda), and Zellweger syndrome.
[0145] The term "spleen disease" refers to a disease of the spleen.
Example of spleen diseases include, but are not limited to,
splenomegaly, spleen cancer, asplenia, spleen trauma, idiopathic
purpura, Felty's syndrome, Hodgkin's disease, and immune-mediated
destruction of the spleen.
[0146] The term "lung disease" or "pulmonary disease" refers to a
disease of the lung. Examples of lung diseases include, but are not
limited to, bronchiectasis, bronchitis, bronchopulmonary dysplasia,
interstitial lung disease, occupational lung disease, emphysema,
cystic fibrosis, acute respiratory distress syndrome (ARDS), severe
acute respiratory syndrome (SARS), asthma (e.g., intermittent
asthma, mild persistent asthma, moderate persistent asthma, severe
persistent asthma), chronic bronchitis, chronic obstructive
pulmonary disease (COPD), emphysema, interstitial lung disease,
sarcoidosis, asbestosis, aspergilloma, aspergillosis, pneumonia
(e.g., lobar pneumonia, multilobar pneumonia, bronchial pneumonia,
interstitial pneumonia), pulmonary fibrosis, pulmonary
tuberculosis, rheumatoid lung disease, pulmonary embolism, and lung
cancer (e.g., non-small-cell lung carcinoma (e.g., adenocarcinoma,
squamous-cell lung carcinoma, large-cell lung carcinoma),
small-cell lung carcinoma).
[0147] A "hematological disease" includes a disease which affects a
hematopoietic cell or tissue. Hematological diseases include
diseases associated with aberrant hematological content and/or
function. Examples of hematological diseases include diseases
resulting from bone marrow irradiation or chemotherapy treatments
for cancer, diseases such as pernicious anemia, hemorrhagic anemia,
hemolytic anemia, aplastic anemia, sickle cell anemia,
sideroblastic anemia, anemia associated with chronic infections
such as malaria, trypanosomiasis, HTV, hepatitis virus or other
viruses, myelophthisic anemias caused by marrow deficiencies, renal
failure resulting from anemia, anemia, polycythemia, infectious
mononucleosis (EVI), acute non-lymphocytic leukemia (ANLL), acute
myeloid leukemia (AML), acute promyelocytic leukemia (APL), acute
myelomonocytic leukemia (AMMoL), polycythemia vera, lymphoma, acute
lymphocytic leukemia (ALL), chronic lymphocytic leukemia, Wilm's
tumor, Ewing's sarcoma, retinoblastoma, hemophilia, disorders
associated with an increased risk of thrombosis, herpes,
thalassemia, antibody-mediated disorders such as transfusion
reactions and erythroblastosis, mechanical trauma to red blood
cells such as micro-angiopathic hemolytic anemias, thrombotic
thrombocytopenic purpura and disseminated intravascular
coagulation, infections by parasites such as Plasmodium, chemical
injuries from, e.g., lead poisoning, and hypersplenism.
[0148] The term "neurological disease" refers to any disease of the
nervous system, including diseases that involve the central nervous
system (brain, brainstem and cerebellum), the peripheral nervous
system (including cranial nerves), and the autonomic nervous system
(parts of which are located in both central and peripheral nervous
system). Neurodegenerative diseases refer to a type of neurological
disease marked by the loss of nerve cells, including, but not
limited to, Alzheimer's disease, Parkinson's disease, amyotrophic
lateral sclerosis, tauopathies (including frontotemporal dementia),
and Huntington's disease. Examples of neurological diseases
include, but are not limited to, headache, stupor and coma,
dementia, seizure, sleep disorders, trauma, infections, neoplasms,
neuro-ophthalmology, movement disorders, demyelinating diseases,
spinal cord disorders, and disorders of peripheral nerves, muscle
and neuromuscular junctions. Addiction and mental illness, include,
but are not limited to, bipolar disorder and schizophrenia, are
also included in the definition of neurological diseases. Further
examples of neurological diseases include acquired epileptiform
aphasia; acute disseminated encephalomyelitis;
adrenoleukodystrophy; agenesis of the corpus callosum; agnosia;
Aicardi syndrome; Alexander disease; Alpers' disease; alternating
hemiplegia; Alzheimer's disease; amyotrophic lateral sclerosis;
anencephaly; Angelman syndrome; angiomatosis; anoxia; aphasia;
apraxia; arachnoid cysts; arachnoiditis; Arnold-Chiari
malformation; arteriovenous malformation; Asperger syndrome; ataxia
telangiectasia; attention deficit hyperactivity disorder; autism;
autonomic dysfunction; back pain; Batten disease; Behcet's disease;
Bell's palsy; benign essential blepharospasm; benign focal;
amyotrophy; benign intracranial hypertension; Binswanger's disease;
blepharospasm; Bloch Sulzberger syndrome; brachial plexus injury;
brain abscess; bbrain injury; brain tumors (including glioblastoma
multiforme); spinal tumor; Brown-Sequard syndrome; Canavan disease;
carpal tunnel syndrome (CTS); causalgia; central pain syndrome;
central pontine myelinolysis; cephalic disorder; cerebral aneurysm;
cerebral arteriosclerosis; cerebral atrophy; cerebral gigantism;
cerebral palsy; Charcot-Marie-Tooth disease; chemotherapy-induced
neuropathy and neuropathic pain; Chiari malformation; chorea;
chronic inflammatory demyelinating polyneuropathy (CIDP); chronic
pain; chronic regional pain syndrome; Coffin Lowry syndrome; coma,
including persistent vegetative state; congenital facial diplegia;
corticobasal degeneration; cranial arteritis; craniosynostosis;
Creutzfeldt-Jakob disease; cumulative trauma disorders; Cushing's
syndrome; cytomegalic inclusion body disease (CIBD);
cytomegalovirus infection; dancing eyes-dancing feet syndrome;
Dandy-Walker syndrome; Dawson disease; De Morsier's syndrome;
Dejerine-Klumpke palsy; dementia; dermatomyositis; diabetic
neuropathy; diffuse sclerosis; dysautonomia; dysgraphia; dyslexia;
dystonias; early infantile epileptic encephalopathy; empty sella
syndrome; encephalitis; encephaloceles; encephalotrigeminal
angiomatosis; epilepsy; Erb's palsy; essential tremor; Fabry's
disease; Fahr's syndrome; fainting; familial spastic paralysis;
febrile seizures; Fisher syndrome; Friedreich's ataxia;
frontotemporal dementia and other "tauopathies"; Gaucher's disease;
Gerstmann's syndrome; giant cell arteritis; giant cell inclusion
disease; globoid cell leukodystrophy; Guillain-Barre syndrome;
HTLV-1 associated myelopathy; Hallervorden-Spatz disease; head
injury; headache; hemifacial spasm; hereditary spastic paraplegia;
heredopathia atactica polyneuritiformis; herpes zoster oticus;
herpes zoster; Hirayama syndrome; HIV-associated dementia and
neuropathy (see also neurological manifestations of AIDS);
holoprosencephaly; Huntington's disease and other polyglutamine
repeat diseases; hydranencephaly; hydrocephalus; hypercortisolism;
hypoxia; immune-mediated encephalomyelitis; inclusion body
myositis; incontinentia pigmenti; infantile; phytanic acid storage
disease; Infantile Refsum disease; infantile spasms; inflammatory
myopathy; intracranial cyst; intracranial hypertension; Joubert
syndrome; Kearns-Sayre syndrome; Kennedy disease; Kinsbourne
syndrome; Klippel Feil syndrome; Krabbe disease; Kugelberg-Welander
disease; kuru; Lafora disease; Lambert-Eaton myasthenic syndrome;
Landau-Kleffner syndrome; lateral medullary (Wallenberg) syndrome;
learning disabilities; Leigh's disease; Lennox-Gastaut syndrome;
Lesch-Nyhan syndrome; leukodystrophy; Lewy body dementia;
lissencephaly; locked-in syndrome; Lou Gehrig's disease (aka motor
neuron disease or amyotrophic lateral sclerosis); lumbar disc
disease; lyme disease-neurological sequelae; Machado-Joseph
disease; macrencephaly; megalencephaly; Melkersson-Rosenthal
syndrome; Menieres disease; meningitis; Menkes disease;
metachromatic leukodystrophy; microcephaly; migraine; Miller Fisher
syndrome; mini-strokes; mitochondrial myopathies; Mobius syndrome;
monomelic amyotrophy; motor neurone disease; moyamoya disease;
mucopolysaccharidoses; multi-infarct dementia; multifocal motor
neuropathy; multiple sclerosis and other demyelinating disorders;
multiple system atrophy with postural hypotension; muscular
dystrophy; myasthenia gravis; myelinoclastic diffuse sclerosis;
myoclonic encephalopathy of infants; myoclonus; myopathy; myotonia
congenital; narcolepsy; neurofibromatosis; neuroleptic malignant
syndrome; neurological manifestations of AIDS; neurological
sequelae of lupus; neuromyotonia; neuronal ceroid lipofuscinosis;
neuronal migration disorders; Niemann-Pick disease;
O'Sullivan-McLeod syndrome; occipital neuralgia; occult spinal
dysraphism sequence; Ohtahara syndrome; olivopontocerebellar
atrophy; opsoclonus myoclonus; optic neuritis; orthostatic
hypotension; overuse syndrome; paresthesia; Parkinson's disease;
paramyotonia congenita; paraneoplastic diseases; paroxysmal
attacks; Parry Romberg syndrome; Pelizaeus-Merzbacher disease;
periodic paralyses; peripheral neuropathy; painful neuropathy and
neuropathic pain; persistent vegetative state; pervasive
developmental disorders; photic sneeze reflex; phytanic acid
storage disease; Pick's disease; pinched nerve; pituitary tumors;
polymyositis; porencephaly; Post-Polio syndrome; postherpetic
neuralgia (PHN); postinfectious encephalomyelitis; postural
hypotension; Prader-Willi syndrome; primary lateral sclerosis;
prion diseases; progressive; hemifacial atrophy; progressive
multifocal leukoencephalopathy; progressive sclerosing
poliodystrophy; progressive supranuclear palsy; pseudotumor
cerebri; Ramsay-Hunt syndrome (Type I and Type II); Rasmussen's
Encephalitis; reflex sympathetic dystrophy syndrome; Refsum
disease; repetitive motion disorders; repetitive stress injuries;
restless legs syndrome; retrovirus-associated myelopathy; Rett
syndrome; Reye's syndrome; Saint Vitus Dance; Sandhoff disease;
Schilder's disease; schizencephaly; septo-optic dysplasia; shaken
baby syndrome; shingles; Shy-Drager syndrome; Sjogren's syndrome;
sleep apnea; Soto's syndrome; spasticity; spina bifida; spinal cord
injury; spinal cord tumors; spinal muscular atrophy; stiff-person
syndrome; stroke; Sturge-Weber syndrome; subacute sclerosing
panencephalitis; subarachnoid hemorrhage; subcortical
arteriosclerotic encephalopathy; sydenham chorea; syncope;
syringomyelia; tardive dyskinesia; Tay-Sachs disease; temporal
arteritis; tethered spinal cord syndrome; Thomsen disease; thoracic
outlet syndrome; tic douloureux; Todd's paralysis; Tourette
syndrome; transient ischemic attack; transmissible spongiform
encephalopathies; transverse myelitis; traumatic brain injury;
tremor; trigeminal neuralgia; tropical spastic paraparesis;
tuberous sclerosis; vascular dementia (multi-infarct dementia);
vasculitis including temporal arteritis; Von Hippel-Lindau Disease
(VHL); Wallenberg's syndrome; Werdnig-Hoffman disease; West
syndrome; whiplash; Williams syndrome; Wilson's disease; and
Zellweger syndrome.
[0149] A "painful condition" includes, but is not limited to,
neuropathic pain (e.g., peripheral neuropathic pain), central pain,
deafferentiation pain, chronic pain (e.g., chronic nociceptive
pain, and other forms of chronic pain such as post-operative pain,
e.g., pain arising after hip, knee, or other replacement surgery),
pre-operative pain, stimulus of nociceptive receptors (nociceptive
pain), acute pain (e.g., phantom and transient acute pain),
noninflammatory pain, inflammatory pain, pain associated with
cancer, wound pain, burn pain, postoperative pain, pain associated
with medical procedures, pain resulting from pruritus, painful
bladder syndrome, pain associated with premenstrual dysphoric
disorder and/or premenstrual syndrome, pain associated with chronic
fatigue syndrome, pain associated with pre-term labor, pain
associated with withdrawl symptoms from drug addiction, joint pain,
arthritic pain (e.g., pain associated with crystalline arthritis,
osteoarthritis, psoriatic arthritis, gouty arthritis, reactive
arthritis, rheumatoid arthritis or Reiter's arthritis), lumbosacral
pain, musculo-skeletal pain, headache, migraine, muscle ache, lower
back pain, neck pain, toothache, dental/maxillofacial pain,
visceral pain and the like. One or more of the painful conditions
contemplated herein can comprise mixtures of various types of pain
provided above and herein (e.g. nociceptive pain, inflammatory
pain, neuropathic pain, etc.). In some embodiments, a particular
pain can dominate. In other embodiments, the painful condition
comprises two or more types of pains without one dominating. A
skilled clinician can determine the dosage to achieve a
therapeutically effective amount for a particular subject based on
the painful condition.
[0150] The term "psychiatric disorder" refers to a disease of the
mind and includes diseases and disorders listed in the Diagnostic
and Statistical Manual of Mental Disorders--Fourth Edition
(DSM-IV), published by the American Psychiatric Association,
Washington D. C. (1994). Psychiatric disorders include, but are not
limited to, anxiety disorders (e.g., acute stress disorder
agoraphobia, generalized anxiety disorder, obsessive-compulsive
disorder, panic disorder, posttraumatic stress disorder, separation
anxiety disorder, social phobia, and specific phobia), childhood
disorders, (e.g., attention-deficit/hyperactivity disorder, conduct
disorder, and oppositional defiant disorder), eating disorders
(e.g., anorexia nervosa and bulimia nervosa), mood disorders (e.g.,
depression, bipolar disorder, cyclothymic disorder, dysthymic
disorder, and major depressive disorder), personality disorders
(e.g., antisocial personality disorder, avoidant personality
disorder, borderline personality disorder, dependent personality
disorder, histrionic personality disorder, narcissistic personality
disorder, obsessive-compulsive personality disorder, paranoid
personality disorder, schizoid personality disorder, and
schizotypal personality disorder), psychotic disorders (e.g., brief
psychotic disorder, delusional disorder, schizoaffective disorder,
schizophreniform disorder, schizophrenia, and shared psychotic
disorder), substance-related disorders (e.g., alcohol dependence,
amphetamine dependence, cannabis dependence, cocaine dependence,
hallucinogen dependence, inhalant dependence, nicotine dependence,
opioid dependence, phencyclidine dependence, and sedative
dependence), adjustment disorder, autism, delirium, dementia,
multi-infarct dementia, learning and memory disorders (e.g.,
amnesia and age-related memory loss), and Tourette's disorder.
[0151] The term "metabolic disorder" refers to any disorder that
involves an alteration in the normal metabolism of carbohydrates,
lipids, proteins, nucleic acids, or a combination thereof. A
metabolic disorder is associated with either a deficiency or excess
in a metabolic pathway resulting in an imbalance in metabolism of
nucleic acids, proteins, lipids, and/or carbohydrates. Factors
affecting metabolism include, and are not limited to, the endocrine
(hormonal) control system (e.g., the insulin pathway, the
enteroendocrine hormones including GLP-1, PYY or the like), the
neural control system (e.g., GLP-1 in the brain), or the like.
Examples of metabolic disorders include, but are not limited to,
diabetes (e.g., type 1 diabetes, type 2 diabetes, gestational
diabetes), hyperglycemia, hyperinsulinemia, insulin resistance, and
obesity.
[0152] The term "thermoplastic elastomer" refers to a material that
is plasticized at a temperature higher than 20.degree. C. (e.g.,
higher than 40.degree. C., higher than 60.degree. C., higher than
100.degree. C., higher than 150.degree. C., or higher than
200.degree. C.), like plastics, and exhibits elastomeric (e.g.,
rubber-like) properties at about 20.degree. C.
[0153] The term "conjugate" refers to the product formed by
covalently attaching two substances. In certain embodiments, a
hydrogen atom of the first substance is removed to form a first
monoradical, a hydrogen atom of the second substance is removed to
form a second monoradical, and the first monoradical and the second
monoradical are directly connected to form the product.
[0154] The term "ambient conditions" refers to 20.degree. C., 1
atmosphere, and 50% relative humidity.
BRIEF DESCRIPTION OF THE DRAWINGS
[0155] FIGS. 1A to 1C. (FIG. 1A) Scheme showing the stepwise
self-assembly of BCPMONs by MON formation followed by block
copolymer phase separation. (FIG. 1B) Schematic and chemical
structures of ligands employed to form MONs. (FIG. 1C) Schematic
representation of the sizes and geometries metal-ligand assemblies
investigated.
[0156] FIGS. 2A to 2C. (FIG. 2A) Synthetic scheme of pyridyl ligand
functionalized poly(methyl methacrylate)-block-poly(n-butyl
acrylate) (PMMA-PBA)-L (-L1, -L2, or -L3). (FIG. 2B) .sup.1H NMR
characterization of the self-assembly of PMMA-PBA-L2 to form 4-arm
star polymers containing a paddlewheel MON core. (FIG. 2C) .sup.1H
NMR characterization of the self-assembly of PMMA-PBA-L3 into
24-arm star polymers with a Fujita sphere MON core.
[0157] FIGS. 3A to 3C. (FIG. 3A) Dynamic light scattering (DLS)
histograms showing the size and size distribution of 4-arm (top)
and 24-arm (bottom) star polymers assembled using PMMA-PBA-L2 and
-L3. (FIG. 3B) Atomic force microscopy (AFM) height images showing
the star polymers nanoparticle containing a Fujita sphere MON core.
(FIG. 3B) Selected area is zoomed in and the height profile for a
selected particle is depicted showing its width and height. (FIG.
3C) Transmission electron microscope image showing the same
particles used in FIG. 3B. Scale bars, 200 nm.
[0158] FIGS. 4A to 4C. Small angle X-ray scattering (top left),
atomic force microscopy (top right), and rheology study of linear
block copolymers and star block copolymers with MONs of different
molecular weights and block volume fractions. (FIG. 4A)
PMMA.sub.4k-PBA.sub.19k. (FIG. 4B) PMMA.sub.8k-PBA.sub.27k. (FIG.
4C) PMMA.sub.8k-PBA.sub.4k. Scale bars: 200 nm.
[0159] FIGS. 5A and 5B. Calculated spinodal curves of star polymer
with 1, 4, and 24 PMMA-PBA arms.
[0160] FIGS. 6A to 6D. (FIG. 6A) The storage and loss moduli of
BCPMON materials over different temperatures showing the transition
between the gel and solution state. (FIG. 6B) SAXS profiles and
pictures (inset) for BCPMONs in 2-ethyl hexanol at 25 and
50.degree. C. (FIG. 6C) SAXS profiles showing the difference in the
d-spacing of phase separation in gels with different MON cores.
(FIG. 6D) The storage moduli and the solution-gel (sol-gel)
transition temperature of gels with MON cores mixed at different
ratios.
[0161] FIG. 7. .sup.1H NMR spectrum showing an example of
ligand-functionalized PMMA-PBA block copolymer.
PMMA.sub.4k-PBA.sub.9K-L.sub.3 is shown. Solvent:
acetonitrile-d.sub.3.
[0162] FIGS. 8A to 8D. .sup.1H NMR spectra comparing the formation
of paddle wheel-like M.sub.2L.sub.4 MON based on small molecules in
DMSO-d.sub.6 (1) and block copolymers in acetonitrile-d.sub.3 (2).
Spectra before (FIGS. 8A and 8B) and after (FIGS. 8C and 8D)
assembly are shown. Block copolymer PMMA.sub.4k-PBA.sub.19k-L2 was
used to obtain the spectra.
[0163] FIGS. 9A to 9D. .sup.1H NMR spectra comparing the formation
of Fujita sphere-like M.sub.12L.sub.24 MON based on small molecules
DMSO-d.sub.6 (1) and block copolymers acetonitrile-d.sub.3 (2).
Spectra before (FIGS. 9A and 9B) and after (FIGS. 9C and 9D)
assembly are shown. Block copolymer PMMA.sub.4k-PBA.sub.19k-L3 was
used to obtain the spectra. The molecular weight of the assembled
star polymer (shown in FIG. 9D) is .about.552,000 (23000.times.24)
Da. Due to this large size, the aromatic resonances from the
M.sub.12L.sub.24 cage are greatly broadened.
[0164] FIG. 10. Atomic force microscopy (AFM) height image of a
linear block copolymer PMMA.sub.4k-PBA.sub.19k coated on silicon
wafer, which demonstrates that no nanoparticles were observed and
rules out the possibility of micelle formation when sample was
prepared (spin-coating a dilute solution).
[0165] FIGS. 11A and 11B. Atomic force microscopy (AFM) phase
images of (FIG. 11A) the linear block copolymer
PMMA.sub.4k-PBA.sub.19k and (FIG. 11B) the star polymer with
M.sub.12L.sub.24 MON core PMMA.sub.4k-PBA.sub.19k-L3 showing the
effect of MON core on the phase separation behavior.
[0166] FIGS. 12A to 12D. Atomic force microscopy (AFM) phase images
of (FIG. 12A) the linear block copolymer PMMA.sub.8k-PBA.sub.27k
and the star polymers PMMA.sub.8k-PBA.sub.27k-L1 (FIG. 12B), -L2
(FIG. 12C), and -L3 (FIG. 12D) with M.sub.1L.sub.4, M.sub.2L.sub.4,
and M.sub.12L.sub.24 MON cores, receptively, showing the effect of
MON core on the phase separation behavior.
[0167] FIGS. 13A to 13D. Atomic force microscopy (AFM) phase images
of (FIG. 13A) the linear block copolymer PMMA.sub.8k-PBA.sub.48k
and the star polymers PMMA.sub.8k-PBA.sub.48k-L1 (FIG. 13B), -L2
(FIG. 13C), and -L3 (FIG. 13D) with M.sub.1L.sub.4, M.sub.2L.sub.4,
and M.sub.12L.sub.24 MON cores, respectively, showing the effect of
MON core on the phase separation behavior.
[0168] FIG. 14. Temperature sweep experiments of BCPMON organogels
with various ratios of M.sub.2L.sub.4 and M.sub.12L.sub.24 MON
junctions shows the moduli and so-gel transition as a function of
temperature.
[0169] FIGS. 15A to 15E. .sup.1H NMR spectra showing the
M.sub.2L.sub.4 and M.sub.12L.sub.24 MONs separately and as a
mixture at room temperature and after heating at 50 and 80.degree.
C. overnight. (FIG. 15A) Spectrum of paddle-wheel M.sub.2L.sub.4
MON; a small amount of extra free ligand was added to enhance
ligand exchange (if any) purposely. (FIG. 15B) Spectrum of Fujita
sphere M.sub.12L.sub.24 MON. (FIG. 15C) Spectrum of the mixture of
FIGS. 15A and 15B. (FIG. 15D) Spectrum showing no changes after the
mixture was heated at 50.degree. C., which indicates that the MONs
maintain their structures at this temperature. (FIG. 15E) New peaks
developed after the mixture was heated at 80.degree. C. overnight,
suggesting possible ligand exchange or degradation to form
ill-defined species.
[0170] FIG. 16. Gel permeation chromatography (GPC) traces of the
PMMA-PBA block copolymer synthesized.
[0171] FIG. 17. IEG synthesis of uniform BDC dimer (L.sub.2) and
tetramer (L.sub.4) ligands as precursors to IEG-polyMOFs.
[0172] FIGS. 18A to 18B. PXRD spectra of polyMOFs derived from
L.sub.2 and L.sub.4 and Zn. (FIG. 18A) L.sub.2-Zn. (FIG. 18B)
L.sub.4-Zn.
[0173] FIGS. 19A to 19C. (FIG. 19A) Synthesis of BCPMON ligands L
PS and L PS. (i) H, 1 eq. of 10% Pd/C; (ii) propargyl bromide,
K.sub.2CO.sub.3, EtOH/DMF; (iii) CuBr, Me.sub.6Tren, THF; (iv) KOH,
DMSO/H.sub.2O. (FIG. 19B) MALDI-TOF spectrum for L.sub.4PS with
selected peaks labeled. (FIG. 19C) .sup.1H NMR (400 MHz) of
L.sub.4-PS in CDCl.sub.3 (solvent labeled with "*").
[0174] FIG. 20. PXRD spectra for BCPMON L.sub.4PS--Zn.
[0175] FIG. 21. SAXS and WAXS data for BCPMON L.sub.4PS--Zn, BCP
L.sub.4PS, and polyMOF L.sub.4-Zn.
[0176] FIGS. 22A to 22D. (FIG. 22A) SEM image of L.sub.4-Zn. (FIG.
22B) SEM image of L.sub.4PS--Zn dried at RT. (FIG. 22C) Positively
stained (RuO.sub.4) TEM image of L.sub.4PS--Zn dried at RT. (FIG.
22D) Schematic of L.sub.4PS--Zn depicting a crystalline polyMOF
domain embedded within a PS matrix.
[0177] FIG. 23. PXRD spectra for BDC-based polyMOF and BCPMON
ligands. 1 is L.sub.2, 2 is L.sub.2PS, 3 is L.sub.4 and 4 is
L.sub.4PS. Note that L.sub.4 is highly hygroscopic.
[0178] FIG. 24. PXRD spectrum for L.sub.4Bn-Zn.
[0179] FIG. 25. PXRD spectra for L.sub.2PS--Zn.
[0180] FIG. 26. DSC data for L.sub.4PS.
[0181] FIG. 27. AFM image of L.sub.4PS--Zn annealed at 120.degree.
C. for 12 hours.
[0182] FIG. 28. N.sub.2 sorption isotherms for L.sub.4-Zn (1) and
L.sub.4PS--Zn (2). Note: we obtained reasonable surface area not
controlling water content which was found to be the optimal
synthetic protocols for MOF-5's gas storage (S. S. Kaye, A. Dailly,
O. M. Yaghi and J. R. Long J. Am. Chem. Soc., 2007, 129,
14176-14177). The low value for L.sub.4PS--Zn is not unexpected due
to the high content of nonporous polymer and high solubility in
organic solvents which made solvent exchange difficult. The
activation at 160.degree. C., above the T.sub.g of polystyrene,
could also lead to incorporation of polymers in to the polyMOF
pores.
[0183] FIG. 29. MALDI-TOF spectra in negative ion mode. Top trace
is L.sub.2PS and bottom trace is L.sub.4PS. Within a 0.1% margin of
error, calculated m/z is 4445.53 for L.sub.2PS and 5063.79 for
L.sub.4PS (35 units of styrene).
[0184] FIG. 30. TEM image of L.sub.4PS--Zn annealed at 120.degree.
C. for 12 hours.
[0185] FIG. 31. DSC trace of L.sub.2.
[0186] FIG. 32. DSC trace of L.sub.2PS.
[0187] FIG. 33. DSC trace of L.sub.4.
[0188] FIG. 34. TGA data for L.sub.2.
[0189] FIG. 35. TGA data for L.sub.2-Zn.
[0190] FIG. 36. TGA data for L.sub.2PS.
[0191] FIG. 37. TGA data for L.sub.4.
[0192] FIG. 38. TGA data for L.sub.4-Zn.
[0193] FIG. 39. TGA data for L.sub.4PS.
[0194] FIG. 40. A schematic of a metal organic nanostructure of
Formula (I-A).
[0195] FIG. 41. A schematic of a metal organic nanostructure of
Formula (I-B).
[0196] FIG. 42. A schematic of a metal organic nanostructure of
Formula (I-C).
[0197] FIG. 43. Representation of a {100} layer of the MOF-5
framework shown along the a-axis (light grey dots: carbon atoms;
dark grey dots: oxygen atoms; tetrahedra: (transition metal
ion)O.sub.4) (Li et al., Nature, 1999, 402, 276).
DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE DISCLOSURE
[0198] We report a stepwise assembly strategy for the integration
of MONs into block copolymers (BCPs). This approach creates `block
co-polyMON` (BCPMON) materials whose microscopic structures and
mechanical properties are readily tunable by adjusting the size and
geometry of the MONs and the composition of the BCPs. In the first
assembly step, BCPs functionalized with a pyridyl ligand on the
chain end form star-shaped polymers triggered by
metal-coordination-induced MON assembly. The type of MON junction
employed precisely determines the number of arms for the star
polymer. In the second step, microphase separation of the BCP is
induced, physically crosslinking the star polymers and producing
the desired BCPMON networks in the bulk (elastomers) or gel state
(organogels). It is demonstrated that, through small changes
programmed in the ligand design, large spherical (e.g.,
M.sub.12L.sub.24) cages, small paddle wheel-like (e.g.,
M.sub.2L.sub.4) cages, or a mixture of both can be incorporated
into BCPMONs, precisely tailoring the microstructure of the
materials including their branch functionality, phase separation
and micro-domain spacing. This versatility enabled us to modulate
the mechanical properties of the obtained materials. Given the
synthetic and functional diversity of MONs and BCPs, the method
described herein should give access to BCPMONs with a wide variety
of properties.
[0199] Also provided herein are BCPMONs comprising a benzene
dicarboxylate (BDC)-based oligomer, a polymer (e.g., PS), and a
transition metal (e.g., Zn) ion. In certain embodiments, this
BCPMON comprises a polyMOF domain embedded in a polymer (e.g., PS)
matrix. This BCPMON may be the first demonstration that a BCP with
a suitably designed polyMOF-forming block can form a composite
material with both highly crystalline polyMOF domains and amorphous
polymer domains.
[0200] The BCPMONs may be useful for gas and energy storage,
catalysis, and/or gas separation.
BCPMOFs (e.g., BCPMONs) and Macromonomers
[0201] In one aspect, the present disclosure provides BCPMOFs
(e.g., BCPMONs). In certain embodiments, the BCPMON comprises:
[0202] (a) a metal organic nanostructure comprising: [0203] (i) x
instances of a transition metal ion, wherein x is an integer
between 2 and 60, inclusive; and [0204] (ii) 2x instances of a
ligand of Formula (A):
[0204] ##STR00011## [0205] wherein: [0206] Ring A is a substituted
or unsubstituted phenyl ring or a substituted or unsubstituted, 5-
or 6-membered, monocyclic heteroaryl ring; [0207] each of X.sup.A,
X.sup.B, X.sup.C, and X.sup.D is independently O, S, N, NR.sup.A1,
C, or CR.sup.A2; [0208] X.sup.E is a bond, N, or CR.sup.A2; [0209]
each instance of R.sup.A1 is independently hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, or a nitrogen protecting group; [0210]
each instance of R.sup.A2 is independently hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.a, --N(R.sup.a).sub.2,
--SR.sup.a, --CN, --SCN, --C(.dbd.NR.sup.a)R.sup.a,
--C(.dbd.NR.sup.a)OR.sup.a, --C(.dbd.NR.sup.a)N(R.sup.a).sub.2,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.aa,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; [0211] each
instance of R.sup.a is independently hydrogen, substituted or
unsubstituted acyl, substituted or unsubstituted alkyl, substituted
or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, a nitrogen protecting
group when attached to a nitrogen atom, an oxygen protecting group
when attached to an oxygen atom, or a sulfur protecting group when
attached to a sulfur atom, or two instances of R.sup.a are joined
to form a substituted or unsubstituted heterocyclic or substituted
or unsubstituted heteroaryl ring; [0212] each instance of R.sup.B
is independently halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.aa,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.aa, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; [0213] m is
0, 1, 2, 3, or 4, as valency permits; [0214] each instance of
R.sup.C is independently halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sup.a, --N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.aa,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.aa, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; [0215] n is
0, 1, 2, 3, or 4, as valency permits; [0216] Z.sup.A is a bond or a
substituted or unsubstituted C.sub.1-4 hydrocarbon chain,
optionally wherein one or more chain atoms are independently
replaced with --C(.dbd.O)--, --O--, --S--, --NR.sup.ZA--, --N.dbd.,
or .dbd.N--, wherein each instance of R.sup.ZA is independently
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a
nitrogen protecting group; and [0217] Z.sup.B is a bond or a
substituted or unsubstituted C.sub.1-4 hydrocarbon chain,
optionally wherein one or more chain atoms are independently
replaced with --C(.dbd.O)--, --O--, --S--, --NR.sup.ZB--, --N.dbd.,
or .dbd.N--, wherein each instance of R.sup.ZB is independently
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a
nitrogen protecting group; [0218] wherein each instance of the
transition metal ion and two instances of the ligand of Formula (A)
form through coordination bonds a coordination complex; and [0219]
wherein each of the coordination bonds is formed between an
instance of the transition metal ion and the nitrogen atom labeled
with 1' or 1'' of an instance of the ligand of Formula (A); and
[0220] (b) two or more instances of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E, wherein: [0221] each
instance of L is independently a bond or a substituted or
unsubstituted C.sub.1-4 hydrocarbon chain, optionally wherein one
or more chain atoms are independently replaced with --C(.dbd.O)--,
--O--, --S--, --NR.sup.L--, --N.dbd., or .dbd.N--, wherein each
instance of R.sup.L is independently hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;
[0222] each instance of R is independently a diradical of a first
polymer, wherein: [0223] the glass transition temperature (T.sub.g)
of each instance of the first polymer is not higher than 20.degree.
C.; and [0224] the number-average molecular weight (M.sub.n) of the
first polymer is between 1,000 g/mol and 1,000,000 g/mol,
inclusive; [0225] each instance of G is independently a diradical
of a second polymer, wherein: [0226] the T.sub.g of each instance
of the second polymer is higher than 20.degree. C.; and [0227] the
M.sub.n of the second polymer is between 300 g/mol and 100,000
g/mol, inclusive; [0228] each instance of p is independently 0, 1,
2, or 3; [0229] each instance of q is independently 0, 1, 2, or 3,
provided that at least one instance of p and q is 1, 2, or 3;
[0230] each instance of u is independently 0, 1, 2, or 3; [0231]
each instance of v is independently 0, 1, 2, or 3; and [0232] each
instance of E is independently hydrogen, halogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sup.a, --N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.aa,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.aa,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; wherein:
[0233] each instance of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E is independently
directly covalently attached to an instance of the ligand of
Formula (A); and
[0234] each two instances of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E are independently
directly covalently attached to the same instance or two different
instances of the ligand of Formula (A).
[0235] In certain embodiments, the maximum outer dimension of the
metal organic nanostructure is between 1 nm and 1,000 nm,
inclusive. In certain embodiments, the maximum outer dimension of
the metal organic nanostructure is between 1 nm and 100 nm,
inclusive.
[0236] In certain embodiments, the BCPMON comprises:
[0237] (a) a metal organic nanostructure comprising: [0238] (i) x
instances of a transition metal ion, wherein x is an integer
between 2 and 60, inclusive; and [0239] (ii) 2x instances of a
ligand of Formula (A):
[0239] ##STR00012## [0240] wherein: [0241] Ring A is a substituted
or unsubstituted phenyl ring or a substituted or unsubstituted, 5-
or 6-membered, monocyclic heteroaryl ring; [0242] each instance of
X.sup.A, X.sup.B, X.sup.C, and X.sup.D is independently O, S, N,
NR.sup.A1, C, or CR.sup.A2; [0243] X.sup.E is a bond, N, or
CR.sup.A2; [0244] each instance of R.sup.A1 is independently
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, or a nitrogen
protecting group; [0245] each instance of R.sup.A2 is independently
hydrogen, halogen, substituted or unsubstituted alkyl, substituted
or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; [0246] each
instance of R.sup.a is independently hydrogen, substituted or
unsubstituted acyl, substituted or unsubstituted alkyl, substituted
or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, a nitrogen protecting
group when attached to a nitrogen atom, an oxygen protecting group
when attached to an oxygen atom, or a sulfur protecting group when
attached to a sulfur atom, or two instances of R.sup.a are joined
to form a substituted or unsubstituted heterocyclic or substituted
or unsubstituted heteroaryl ring; [0247] each instance of R.sup.B
is independently halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; [0248] m is
0, 1, 2, 3, or 4, as valency permits; [0249] each instance of
R.sup.C is independently halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sup.a, --N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.aa,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; [0250] n is
0, 1, 2, 3, or 4, as valency permits; [0251] Z.sup.A is a bond or a
substituted or unsubstituted C.sub.1-4 hydrocarbon chain,
optionally wherein one or more chain atoms are independently
replaced with --C(.dbd.O)--, --O--, --S--, --NR.sup.ZA--, --N.dbd.,
or .dbd.N--, wherein each instance of R.sup.ZA is independently
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a
nitrogen protecting group; and [0252] Z.sup.B is a bond or a
substituted or unsubstituted C.sub.1-4 hydrocarbon chain,
optionally wherein one or more chain atoms are independently
replaced with --C(.dbd.O)--, --O--, --S--, --NR.sup.ZB--, --N.dbd.,
or .dbd.N--, wherein each instance of R.sup.ZB is independently
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a
nitrogen protecting group; [0253] wherein each instance of the
transition metal ion and two instances of the ligand of Formula (A)
form through coordination bonds a coordination complex; [0254]
wherein each of the coordination bonds is formed between an
instance of the transition metal ion and the nitrogen atom labeled
with 1' or 1'' of an instance of the ligand of Formula (A); and
[0255] wherein the maximum outer dimension of the metal organic
nanostructure is between 1 nm and 100 nm, inclusive; and
[0256] (b) two or more instances of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E, wherein: [0257] each
instance of L is independently a bond or a substituted or
unsubstituted C.sub.1-4 hydrocarbon chain, optionally wherein one
or more chain atoms are independently replaced with --C(.dbd.O)--,
--O--, --S--, --NR.sup.L--, --N.dbd., or .dbd.N--, wherein each
instance of R.sup.L is independently hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;
[0258] each instance of R is independently a diradical of a first
polymer, wherein: [0259] the glass transition temperature (T.sub.g)
of each instance of the first polymer is not higher than 20.degree.
C.; and [0260] the number-average molecular weight (M.sub.n) of the
first polymer is between 1,000 g/mol and 1,000,000 g/mol,
inclusive; [0261] each instance of G is independently a diradical
of a second polymer, wherein: [0262] the T.sub.g of each instance
of the second polymer is higher than 20.degree. C.; and [0263] the
M.sub.n of the second polymer is between 300 g/mol and 100,000
g/mol, inclusive; [0264] each instance of p is independently 1, 2,
or 3; [0265] each instance of q is independently 1, 2, or 3; [0266]
each instance of u is independently 0, 1, 2, or 3; [0267] each
instance of v is independently 0, 1, 2, or 3; and [0268] each
instance of E is independently hydrogen, halogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sup.a, --N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; wherein:
[0269] each instance of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E is independently
directly covalently attached to an instance of the ligand of
Formula (A); and
[0270] each two instances of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E are independently
directly covalently attached to the same instance or two different
instances of the ligand of Formula (A).
[0271] In certain embodiments, the BCPMON comprises:
[0272] (a) a metal organic nanostructure comprising: [0273] (i) a
transition metal ion; and [0274] (ii) four instances of a ligand of
Formula (B):
[0274] ##STR00013## [0275] wherein: [0276] Ring A is a substituted
or unsubstituted phenyl ring or a substituted or unsubstituted, 5-
or 6-membered, monocyclic heteroaryl ring; [0277] each of X.sup.A,
X.sup.B, X.sup.C, and X.sup.D is independently O, S, N, NR.sup.A1,
C, or CR.sup.A2; [0278] X.sup.E is a bond, N, or CR.sup.A2; [0279]
each instance of R.sup.A1 is independently hydrogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, or a nitrogen protecting group; [0280]
each instance of R.sup.A2 is independently hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.a, --N(R.sup.a).sub.2,
--SR.sup.a, --CN, --SCN, --C(.dbd.NR.sup.a)R.sup.a,
--C(.dbd.NR.sup.a)OR.sup.a, --C(.dbd.NR.sup.a)N(R.sup.a).sub.2,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; [0281] each
instance of R.sup.a is independently hydrogen, substituted or
unsubstituted acyl, substituted or unsubstituted alkyl, substituted
or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, a nitrogen protecting
group when attached to a nitrogen atom, an oxygen protecting group
when attached to an oxygen atom, or a sulfur protecting group when
attached to a sulfur atom, or two instances of R.sup.a are joined
to form a substituted or unsubstituted heterocyclic or substituted
or unsubstituted heteroaryl ring; [0282] each instance of R.sup.B
is independently halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; [0283] m is
0, 1, 2, 3, or 4, as valency permits; [0284] Z.sup.A is a bond or a
substituted or unsubstituted C.sub.1-4 hydrocarbon chain,
optionally wherein one or more chain atoms are independently
replaced with --C(.dbd.O)--, --O--, --S--, --NR.sup.ZA--, --N.dbd.,
or .dbd.N--, wherein each instance of R.sup.ZA is independently
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a
nitrogen protecting group; and [0285] wherein the transition metal
ion and the four instances of the ligand of Formula (B) form
through coordination bonds a coordination complex; [0286] wherein
each of the coordination bonds is formed between the transition
metal ion and the nitrogen atom labeled with 1' of each instance of
the ligand of Formula (B); and [0287] wherein the maximum outer
dimension of the metal organic nanostructure is between about 1 nm
and about 100 nm, inclusive; and
[0288] (b) two or more instances of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E, wherein: [0289] each
instance of L is independently a bond or a substituted or
unsubstituted C.sub.1-4 hydrocarbon chain, optionally wherein one
or more chain atoms are independently replaced with --C(.dbd.O)--,
--O--, --S--, --NR.sup.L--, --N.dbd., or .dbd.N--, wherein each
instance of R.sup.L is independently hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;
[0290] each instance of R is independently a diradical of a first
polymer, wherein: [0291] the glass transition temperature (T.sub.g)
of each instance of the first polymer is not higher than 20.degree.
C.; and [0292] the number-average molecular weight (M.sub.n) of the
first polymer is between 1,000 g/mol and 1,000,000 g/mol,
inclusive; [0293] each instance of G is independently a diradical
of a second polymer, wherein: [0294] the T.sub.g of each instance
of the second polymer is higher than 20.degree. C.; and [0295] the
M.sub.n of the second polymer is between 300 g/mol and 100,000
g/mol, inclusive; [0296] each instance of p is independently 0, 1,
2, or 3; [0297] each instance of q is independently 0, 1, 2, or 3,
provided that at least one instance of p and q is 1, 2, or 3;
[0298] each instance of u is independently 0, 1, 2, or 3; [0299]
each instance of v is independently 0, 1, 2, or 3; and [0300] each
instance of E is independently hydrogen, halogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sup.a, --N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; wherein:
[0301] each instance of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E is independently
directly covalently attached to an instance the ligand of Formula
(B); and
[0302] each two instances of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E are independently
directly covalently attached to the same instance or two different
instances of the ligand of Formula (B).
[0303] In certain embodiments, the BCPMON comprises:
[0304] (a) a metal organic nanostructure comprising: [0305] (i) a
transition metal ion; and [0306] (ii) four instances of a ligand of
Formula (B):
[0306] ##STR00014## [0307] wherein: [0308] Ring A is a substituted
or unsubstituted phenyl ring or a substituted or unsubstituted, 5-
or 6-membered, monocyclic heteroaryl ring; [0309] each instance of
X.sup.A, X.sup.B, X.sup.C, and X.sup.D is independently O, S, N,
NR.sup.A1, C, or CR.sup.A2; [0310] X.sup.E is a bond, N, or
CR.sup.A2; [0311] each instance of R.sup.A1 is independently
hydrogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, or a nitrogen
protecting group; [0312] each instance of R.sup.A2 is independently
hydrogen, halogen, substituted or unsubstituted alkyl, substituted
or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; [0313] each
instance of R.sup.a is independently hydrogen, substituted or
unsubstituted acyl, substituted or unsubstituted alkyl, substituted
or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, a nitrogen protecting
group when attached to a nitrogen atom, an oxygen protecting group
when attached to an oxygen atom, or a sulfur protecting group when
attached to a sulfur atom, or two instances of R.sup.a are joined
to form a substituted or unsubstituted heterocyclic or substituted
or unsubstituted heteroaryl ring; [0314] each instance of R.sup.B
is independently halogen, substituted or unsubstituted alkyl,
substituted or unsubstituted alkenyl, substituted or unsubstituted
alkynyl, substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; [0315] m is
0, 1, 2, 3, or 4, as valency permits; [0316] Z.sup.A is a bond or a
substituted or unsubstituted C.sub.1-4 hydrocarbon chain,
optionally wherein one or more chain atoms are independently
replaced with --C(.dbd.O)--, --O--, --S--, --NR.sup.ZA--, --N.dbd.,
or .dbd.N--, wherein each instance of R.sup.ZA is independently
hydrogen, substituted or unsubstituted C.sub.1-6 alkyl, or a
nitrogen protecting group; and [0317] wherein the transition metal
ion and the four instances of at least one instance of the ligand
of Formula (B) form through coordination bonds a coordination
complex; [0318] wherein each of the coordination bonds is formed
between the transition metal ion and the nitrogen atom labeled with
1' of each instance of at least one instance of the ligand of
Formula (B); and [0319] wherein the maximum outer dimension of the
metal organic nanostructure is between about 1 nm and about 100 nm,
inclusive; and
[0320] (b) two or more instances of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E, wherein: [0321] each
instance of L is independently a bond or a substituted or
unsubstituted C.sub.1-4 hydrocarbon chain, optionally wherein one
or more chain atoms are independently replaced with --C(.dbd.O)--,
--O--, --S--, --NR.sup.L--, --N.dbd., or .dbd.N--, wherein each
instance of R.sup.L is independently hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;
[0322] each instance of R is independently a diradical of a first
polymer, wherein: [0323] the glass transition temperature (T.sub.g)
of each instance of the first polymer is not higher than 20.degree.
C.; and [0324] the number-average molecular weight (M.sub.n) of the
first polymer is between 1,000 g/mol and 1,000,000 g/mol,
inclusive; [0325] each instance of G is independently a diradical
of a second polymer, wherein: [0326] the T.sub.g of each instance
of the second polymer is higher than 20.degree. C.; and [0327] the
M.sub.n of the second polymer is between 300 g/mol and 100,000
g/mol, [0328] inclusive; [0329] each instance of p is independently
1, 2, or 3; [0330] each instance of q is independently 1, 2, or 3;
[0331] each instance of u is independently 0, 1, 2, or 3; [0332]
each instance of v is independently 0, 1, 2, or 3; and [0333] each
instance of E is independently hydrogen, halogen, substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl,
substituted or unsubstituted alkynyl, substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sup.a, --N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; wherein:
[0334] each instance of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E is independently
directly covalently attached to an instance of at least one
instance of the ligand of Formula (B); and
[0335] each two instances of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E are independently
directly covalently attached to the same instance or two different
instances of at least one instance of the ligand of Formula
(B).
[0336] In certain embodiments, the BCPMON comprises: [0337] (i) y
instances of a transition metal ion, wherein y is an integer
between 1 and 1,000, inclusive; and [0338] (ii) z instances of a
ligand of Formula (C):
[0338] ##STR00015## [0339] wherein: [0340] z is an integer between
2 and 200, inclusive; [0341] s is an integer between 2 and 10,
inclusive; [0342] each instance of RD is independently hydrogen,
halogen, substituted or unsubstituted C.sub.1-6 alkyl, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.aa,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; [0343] each
instance of T is independently a bond or a substituted or
unsubstituted C.sub.1-50 hydrocarbon chain, optionally wherein one
or more chain atoms are independently replaced with --C(.dbd.O)--,
--O--, --S--, --NR.sup.T--, --N.dbd., or .dbd.N--, wherein each
instance of R.sup.T is independently hydrogen, substituted or
unsubstituted C.sub.1-6 alkyl, or a nitrogen protecting group;
[0344] W is substituted or unsubstituted, C.sub.1-200 alkylene,
substituted or unsubstituted, C.sub.2-200 alkenylene, substituted
or unsubstituted, C.sub.2-200 alkynylene, substituted or
unsubstituted, C.sub.2-200 heteroalkylene, substituted or
unsubstituted, C.sub.2-200 heteroalkenylene, or C.sub.2-200
heteroalkynylene, wherein: [0345] optionally one or more carbons in
each instance of the substituted or unsubstituted, C.sub.1-200
alkylene, substituted or unsubstituted, C.sub.2-200 alkenylene,
substituted or unsubstituted, C.sub.2-200 alkynylene, substituted
or unsubstituted, C.sub.2-200 heteroalkylene, substituted or
unsubstituted, C.sub.2-200 heteroalkenylene, and C.sub.2-200
heteroalkynylene are independently replaced with substituted or
unsubstituted carbocyclylene, substituted or unsubstituted
heterocyclylene, substituted or unsubstituted arylene, or
substituted or unsubstituted heteroarylene; and [0346] optionally
one or more heteroatoms in each instance of the substituted or
unsubstituted, C.sub.2-200 heteroalkylene, substituted or
unsubstituted, C.sub.2-200 heteroalkenylene, and substituted or
unsubstituted, C.sub.2-.sub.200 heteroalkynylene are independently
replaced with substituted or unsubstituted carbocyclylene,
substituted or unsubstituted heterocyclylene, substituted or
unsubstituted arylene, or substituted or unsubstituted
heteroarylene; [0347] each instance of R is independently a
diradical of a first polymer, wherein: [0348] the glass transition
temperature (T.sub.g) of each instance of the first polymer is not
higher than 20.degree. C.; and [0349] the number-average molecular
weight (M.sub.n) of the first polymer is between 1,000 g/mol and
1,000,000 g/mol, inclusive; [0350] each instance of G is
independently a diradical of a second polymer, wherein: [0351] the
T.sub.g of each instance of the second polymer is higher than
20.degree. C.; and [0352] the M.sub.n of the second polymer is
between 300 g/mol and 100,000 g/mol, inclusive; [0353] each
instance of p is independently 0, 1, 2, or 3; [0354] each instance
of q is independently 0, 1, 2, or 3, provided that at least one
instance of p and q is 1, 2, or 3; [0355] each instance of u is
independently 0, 1, 2, or 3; [0356] each instance of v is
independently 0, 1, 2, or 3; and [0357] each instance of E is
independently hydrogen, halogen, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl,
--OR.sup.a, --N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2; and [0358]
each instance of R.sup.a is independently hydrogen, substituted or
unsubstituted acyl, substituted or unsubstituted alkyl, substituted
or unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, a nitrogen protecting
group when attached to a nitrogen atom, an oxygen protecting group
when attached to an oxygen atom, or a sulfur protecting group when
attached to a sulfur atom, or two instances of R.sup.a are joined
to form a substituted or unsubstituted heterocyclic or substituted
or unsubstituted heteroaryl ring; [0359] wherein each instance of
the transition metal ion and at least one instance of the ligand of
Formula (C) form through one or more coordination bonds a
coordination complex; and [0360] wherein each of the coordination
bonds is formed between an instance of the transition metal ion and
an instance of the oxygen atom labeled with "*"
[0361] Another aspect of the present disclosure relates to
macromonomers. In certain embodiments, the macromonomer is Formula
(L):
##STR00016##
wherein:
[0362] Ring A is a substituted or unsubstituted phenyl ring or a
substituted or unsubstituted, 5- or 6-membered, monocyclic
heteroaryl ring;
[0363] each of X.sup.A, X.sup.B, X.sup.C, and X.sup.D is
independently O, S, N, NR.sup.A1, C, or CR.sup.A2
[0364] X.sup.E is a bond, N, or CR.sup.A2
[0365] each instance of R.sup.A1 is independently hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, or a nitrogen protecting group;
[0366] each instance of R.sup.A2 is independently hydrogen,
halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2;
[0367] each instance of R.sup.a is independently hydrogen,
substituted or unsubstituted acyl, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, a
nitrogen protecting group when attached to a nitrogen atom, an
oxygen protecting group when attached to an oxygen atom, or a
sulfur protecting group when attached to a sulfur atom, or two
instances of R.sup.a are joined to form a substituted or
unsubstituted heterocyclic or substituted or unsubstituted
heteroaryl ring;
[0368] each instance of R.sup.B is independently halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.a, --N(R.sup.a).sub.2,
--SR.sup.a, --CN, --SCN, --C(.dbd.NR.sup.a)R.sup.a,
--C(.dbd.NR.sup.a)OR.sup.a, --C(.dbd.NR.sup.a)N(R.sup.a).sub.2,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2;
[0369] m is 0, 1, 2, 3, or 4, as valency permits;
[0370] each instance of R.sup.C is independently halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.a, --N(R.sup.a).sub.2,
--SR.sup.a, --CN, --SCN, --C(.dbd.NR.sup.a)R.sup.a,
--C(.dbd.NR.sup.a)OR.sup.a, --C(.dbd.NR.sup.a)N(R.sup.a).sub.2,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2;
[0371] n is 0, 1, 2, 3, or 4, as valency permits;
[0372] Z.sup.A is a bond or a substituted or unsubstituted
C.sub.1-4 hydrocarbon chain, optionally wherein one or more chain
atoms are independently replaced with --C(.dbd.O)--, --O--, --S--,
--NR.sup.ZA--, --N.dbd., or .dbd.N--, wherein each instance of
R.sup.ZA is independently hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, or a nitrogen protecting group;
[0373] Z.sup.B is a bond or a substituted or unsubstituted
C.sub.1-4 hydrocarbon chain, optionally wherein one or more chain
atoms are independently replaced with --C(.dbd.O)--, --O--, --S--,
--NR.sup.ZB--, --N.dbd., or .dbd.N--, wherein each instance of
R.sup.ZB is independently hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, or a nitrogen protecting group;
[0374] r is 1, 2, or 3;
[0375] each instance of L is independently a bond or a substituted
or unsubstituted C.sub.1-4 hydrocarbon chain, optionally wherein
one or more chain atoms are independently replaced with
--C(.dbd.O)--, --O--, --S--, --NR.sup.L--, --N.dbd., or .dbd.N--,
wherein each instance of R.sup.L is independently hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen
protecting group;
[0376] each instance of R is independently a diradical of a first
polymer, wherein: [0377] the glass transition temperature (T.sub.g)
of each instance of the first polymer is not higher than 20.degree.
C.; and [0378] the number-average molecular weight (M.sub.n) of the
first polymer is between 1,000 g/mol and 1,000,000 g/mol,
inclusive;
[0379] each instance of G is independently a diradical of a second
polymer, wherein: [0380] the T.sub.g of each instance of the second
polymer is higher than 20.degree. C.; and [0381] the M.sub.n of the
second polymer is between 300 g/mol and 100,000 g/mol,
inclusive;
[0382] each instance of p is independently 0, 1, 2, or 3;
[0383] each instance of q is independently 0, 1, 2, or 3, provided
that at least one instance of p and q is 1, 2, or 3;
[0384] each instance of u is independently 0, 1, 2, or 3;
[0385] each instance of v is independently 0, 1, 2, or 3; and
[0386] each instance of E is independently hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.a, --N(R.sup.a).sub.2,
--SR.sup.a, --CN, --SCN, --C(.dbd.NR.sup.a)R.sup.aa,
--C(.dbd.NR.sup.a)OR.sup.aa, --C(.dbd.NR.sup.a)N(R.sup.a).sub.2,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.aa,
--C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.aa,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2.
[0387] In certain embodiments, the macromonomer is of Formula
(M):
##STR00017##
wherein:
[0388] Ring A is a substituted or unsubstituted phenyl ring or a
substituted or unsubstituted, 5- or 6-membered, monocyclic
heteroaryl ring;
[0389] each of X.sup.A, X.sup.B, X.sup.C, and X.sup.D is
independently O, S, N, NR.sup.A1, C, or CR.sup.A2
[0390] X.sup.E is a bond, N, or CR.sup.A2
[0391] each instance of R.sup.A1 is independently hydrogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, or a nitrogen protecting group;
[0392] each instance of R.sup.A2 is independently hydrogen,
halogen, substituted or unsubstituted alkyl, substituted or
unsubstituted alkenyl, substituted or unsubstituted alkynyl,
substituted or unsubstituted carbocyclyl, substituted or
unsubstituted heterocyclyl, substituted or unsubstituted aryl,
substituted or unsubstituted heteroaryl, --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2;
[0393] each instance of R.sup.a is independently hydrogen,
substituted or unsubstituted acyl, substituted or unsubstituted
alkyl, substituted or unsubstituted alkenyl, substituted or
unsubstituted alkynyl, substituted or unsubstituted carbocyclyl,
substituted or unsubstituted heterocyclyl, substituted or
unsubstituted aryl, substituted or unsubstituted heteroaryl, a
nitrogen protecting group when attached to a nitrogen atom, an
oxygen protecting group when attached to an oxygen atom, or a
sulfur protecting group when attached to a sulfur atom, or two
instances of R.sup.a are joined to form a substituted or
unsubstituted heterocyclic or substituted or unsubstituted
heteroaryl ring;
[0394] each instance of R.sup.B is independently halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.a, --N(R.sup.a).sub.2,
--SR.sup.a, --CN, --SCN, --C(.dbd.NR.sup.a)R.sup.a,
--C(.dbd.NR.sup.a)OR.sup.a, --C(.dbd.NR.sup.a)N(R.sup.a).sub.2,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2;
[0395] m is 0, 1, 2, 3, or 4, as valency permits;
[0396] Z.sup.A is a bond or a substituted or unsubstituted
C.sub.1-4 hydrocarbon chain, optionally wherein one or more chain
atoms are independently replaced with --C(.dbd.O)--, --O--, --S--,
--NR.sup.ZA--, --N.dbd., or .dbd.N--, wherein each instance of
R.sup.ZA is independently hydrogen, substituted or unsubstituted
C.sub.1-6 alkyl, or a nitrogen protecting group;
[0397] r is 1, 2, or 3;
[0398] each instance of L is independently a bond or a substituted
or unsubstituted C.sub.1-4 hydrocarbon chain, optionally wherein
one or more chain atoms are independently replaced with
--C(.dbd.O)--, --O--, --S--, --NR.sup.L--, --N.dbd., or .dbd.N--,
wherein each instance of R.sup.L is independently hydrogen,
substituted or unsubstituted C.sub.1-6 alkyl, or a nitrogen
protecting group;
[0399] each instance of R is independently a diradical of a first
polymer, wherein: [0400] the glass transition temperature (T.sub.g)
of each instance of the first polymer is not higher than 20.degree.
C.; and [0401] the number-average molecular weight (M.sub.n) of the
first polymer is between 1,000 g/mol and 1,000,000 g/mol,
inclusive;
[0402] each instance of G is independently a diradical of a second
polymer, wherein: [0403] the T.sub.g of each instance of the second
polymer is higher than 20.degree. C.; and [0404] the M.sub.n of the
second polymer is between 300 g/mol and 100,000 g/mol,
inclusive;
[0405] each instance of p is independently 0, 1, 2, or 3;
[0406] each instance of q is independently 0, 1, 2, or 3, provided
that at least one instance of p and q is 1, 2, or 3;
[0407] each instance of u is independently 0, 1, 2, or 3;
[0408] each instance of v is independently 0, 1, 2, or 3; and
[0409] each instance of E is independently hydrogen, halogen,
substituted or unsubstituted alkyl, substituted or unsubstituted
alkenyl, substituted or unsubstituted alkynyl, substituted or
unsubstituted carbocyclyl, substituted or unsubstituted
heterocyclyl, substituted or unsubstituted aryl, substituted or
unsubstituted heteroaryl, --OR.sup.a, --N(R.sup.a).sub.2,
--SR.sup.a, --CN, --SCN, --C(.dbd.NR.sup.a)R.sup.a,
--C(.dbd.NR.sup.a)OR.sup.a, --C(.dbd.NR.sup.a)N(R.sup.a).sub.2,
--C(.dbd.O)R.sup.a, --C(.dbd.O)OR.sup.a,
--C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2.
[0410] In certain embodiments, each instance of p is independently
1, 2, or 3; and each instance of q is independently 1, 2, or 3.
[0411] The BCPMONs described herein may include metal organic
nanostructures, such as nanospheres, nano-paddlewheels, and
nano-squares. Fujita et al. have reported banana-shaped organic
molecules that self-organize into "Fujita spheres," which are
finite, spherical coordination networks with a outer dimension in
the order of nanometers (e.g., Tominaga et al., Angew. Chem., Int.
Ed., 2004, 43, 5621-5625; Bunzen et al. Angew. Chem., Int. Ed.
2012, 51, 3161; Sun et al., Science, 2010, 328, 1144). One of such
reported Fujita spheres consists of 12 equivalents of a central
metal ion (e.g., Pd(II)) and 24 equivalents of a bidentate ligand
and has cuboctahedral symmetry. Hupp et al. has reported
metal-organic frameworks prepared from a hexacarboxylated ligand
and a transition metal ion (e.g., Cu(II) or Zn(II)) (Eryazici et
al., Crystal Growth & Design, 2012, 12, 1075).
[0412] In certain embodiments, the x instances of the transition
metal ion and the 2x instances of the ligand of Formula (A) form
through the coordination bonds a substantially spherical structure
(e.g., nanosphere). In certain embodiments, the nanosphere
comprises:
[0413] (i) a plurality of a transition metal ion; and
[0414] (ii) a plurality of a ligand;
[0415] wherein each instance of the transition metal ion and two or
more instances of the ligand form through coordination bonds a
coordination complex;
[0416] wherein the plurality of a transition metal ion and the
plurality of a ligand form through the coordination bonds one
substantially spherical structure; and
[0417] wherein the maximum outer dimension of the nanosphere is
between about 1 nm and about 100 nm, inclusive.
[0418] In certain embodiments, the x instances of the transition
metal ion and the 2x instances of the ligand of Formula (A) form
through the coordination bonds a substantially paddlewheel
structure (e.g., nano-paddlewheel). In certain embodiments, the
nano-paddlewheel comprises:
[0419] (i) a plurality of a transition metal ion; and
[0420] (ii) a plurality of a ligand;
[0421] wherein each instance of the transition metal ion and two or
more instances of the ligand form through coordination bonds a
coordination complex;
[0422] wherein the plurality of a transition metal ion and the
plurality of a ligand form through the coordination bonds one
substantially paddlewheel structure; and
[0423] wherein the maximum outer dimension of the nano-paddlewheel
is between about 1 nm and about 100 nm, inclusive.
[0424] the x instances of the transition metal ion and the 2x
instances of the ligand of Formula (A) or (B) form through the
coordination bonds a substantially square structure (e.g.,
nano-square). In certain embodiments, the nano-square
comprises:
[0425] (i) a plurality of a transition metal ion; and
[0426] (ii) a plurality of a ligand;
[0427] wherein each instance of the transition metal ion and two or
more instances of the ligand form through coordination bonds a
coordination complex;
[0428] wherein the plurality of a transition metal ion and the
plurality of a ligand form through the coordination bonds one
substantially square structure; and
[0429] wherein the maximum outer dimension of the nano-square is
between about 1 nm and about 100 nm, inclusive.
[0430] In certain embodiments, each instance of the ligand is a
monodentate ligand. In certain embodiments, each instance of the
ligand is a polydentate (e.g., bidentate, tridentate, or
tetradentate) ligand. In certain embodiments, each instance of the
ligand comprises two or more pyridinyl moieties. In certain
embodiments, each instance of the ligand comprises at least a first
pyridinyl moiety and second pyridinyl moiety, wherein the angle
(bite angle) between (1) the lone electron pair of the nitrogen
atom of the first pyridinyl moiety and (2) the lone electron pair
of the nitrogen atom of the second pyridinyl moiety, along the long
axes of the lone electron pairs, is between 30.degree. and
180.degree., inclusive, when the ligand is in the minimum energy
conformation. In certain embodiments, the bite angle is between
60.degree. and 160.degree., inclusive (e.g., about 90.degree.,
about 120.degree., about 127.degree., or about 149.degree.). In
certain embodiments, each instance of the ligand is a polydentate
ligand, wherein the shortest distance between two chelation sites
of the ligand is between about 5 .ANG. and about 20 .ANG. (e.g.,
between about 5 .ANG. and about 10 .ANG.), inclusive, when the
ligand is in the minimum energy conformation.
[0431] In certain embodiments, a metal organic nanostructure
described herein comprises x instances of a transition metal ion
and 2x instances of a ligand of Formula (A):
##STR00018##
[0432] A metal organic nanostructure described herein includes x
instances of a transition metal ion. In certain embodiments, all
instances of the transition metal ion in a metal organic
nanostructure are the same. In certain embodiments, x is an integer
(e.g., an even integer) between 2 and 48, inclusive. In certain
embodiments, x is an integer (e.g., an even integer) between 2 and
30, inclusive. In certain embodiments, x is an integer (e.g., an
even integer) between 2 and 24, inclusive. In certain embodiments,
x is an integer (e.g., an even integer) between 2 and 18,
inclusive. In certain embodiments, x is 2. In certain embodiments,
x is 4. In certain embodiments, x is 6. In certain embodiments, x
is 12. In certain embodiments, x is 18. In certain embodiments, x
is 24. In certain embodiments, x is 30. In certain embodiments, x
is 48. In certain embodiments, x is 60. In certain embodiments, x
is 12; and the nanostructure is a nanosphere. In certain
embodiments, x is 24; and the nanostructure is a nanosphere. In
certain embodiments, x is 2; and the nanostructure is a
nano-paddlewheel.
[0433] In certain embodiments, each instance of the transition
metal ion is the same. In certain embodiments, at least two
instances of the transition metal ion or transition metal salt are
different from each other. In certain embodiments, at least one
instance of the transition metal ion or transition metal salt
comprises Pd (e.g., Pd(II)). In certain embodiments, each instance
of the transition metal ion or transition metal salt comprises Pd
(e.g., Pd(II)). In certain embodiments, at least one instance of
the transition metal ion or transition metal salt comprises Rh
(e.g., Rh(I)). In certain embodiments, at least one instance of the
transition metal ion or transition metal salt comprises Ir (e.g.,
Ir(I)). In certain embodiments, at least one instance of the
transition metal ion or transition metal salt comprises Ni (e.g.,
Ni(II)). In certain embodiments, at least one instance of the
transition metal ion or transition metal salt comprises Pt (e.g.,
Pt(II)). In certain embodiments, at least one instance of the
transition metal ion or transition metal salt comprises Fe (e.g.,
Fe(II) or Fe(III)). In certain embodiments, at least one instance
of the transition metal ion or transition metal salt comprises Au
(e.g., Au(III)). In certain embodiments, at least one instance of
the transition metal ion or transition metal salt comprises Cd
(e.g., Cd(II)), Co (e.g., Co(III)), or Cu (e.g., Cu(I) or Cu(II)).
In certain embodiments, at least one instance of the transition
metal ion or transition metal salt comprises Zn(II). In certain
embodiments, each instance of the transition metal ion or
transition metal salt comprises Zn(II). In certain embodiments, at
least one instance of the transition metal ion or transition metal
salt does not comprise Zn(II).
[0434] In certain embodiments, all instances of the ligand of
Formula (A) in a metal organic nanostructure are the same. In other
embodiments, at least two instances of the ligand of Formula (A) in
a metal organic nanostructure are different. In certain
embodiments, all instances of the ligand of Formula (B) in a metal
organic nanostructure are the same. In other embodiments, at least
two instances of the ligand of Formula (B) in a metal organic
nanostructure are different. In certain embodiments, all instances
of the ligand of Formula (C) in a metal organic nanostructure are
the same. In other embodiments, at least two instances of the
ligand of Formula (C) in a metal organic nanostructure are
different.
[0435] Formula (A) or (B) includes Ring A that includes X.sup.A,
X.sup.B, X.sup.C, X.sup.D, and X.sup.E in the ring system and is
unsubstituted (e.g., each instance of R.sup.A1 and R.sup.A2 is
hydrogen) or substituted with one or more substituents R.sup.A1
and/or R.sup.A2 (e.g., at least one instance of R.sup.A1 or
R.sup.A2 is not hydrogen). In certain embodiments, X.sup.E is a
bond. In certain embodiments, X.sup.E is N, C, or CR.sup.A2. In
certain embodiments, each instance of X.sup.A, X.sup.B, X.sup.C,
X.sup.D, and X.sup.E is independently C or CR.sup.A2, and Ring A is
a substituted or unsubstituted phenyl ring. In certain embodiments,
Ring A is of the formula:
##STR00019##
In certain embodiments, Ring A is of the formula:
##STR00020##
In certain embodiments, Ring A is of the formula:
##STR00021##
In certain embodiments, Ring A is of the formula:
##STR00022##
[0436] In certain embodiments, each instance of X.sup.A, X.sup.B,
X.sup.C, and X.sup.D is independently O, S, N, NR.sup.A1, C, or
CR.sup.A2; at least one of X.sup.A, X.sup.B, X.sup.C, and X.sup.D
is not C or CR.sup.A2; X.sup.E is a bond; and Ring A is a
substituted or unsubstituted, 5-membered, monocyclic heteroaryl
ring. In certain embodiments, Ring A is a substituted or
unsubstituted furanyl, substituted or unsubstituted thienyl, or
substituted or unsubstituted pyrrolyl ring. In certain embodiments,
Ring A is of the formula:
##STR00023##
In certain embodiments, Ring A is a pyrazolyl, imidazolyl,
oxazolyl, isoxazolyl, thiazolyl, or isothiazolyl ring, each of
which is unsubstituted or substituted with R.sup.A2. In certain
embodiments, each instance of X.sup.A, X.sup.B, X.sup.C, and
X.sup.D is independently O, S, N, NR.sup.A1, C, or CR.sup.A;
X.sup.E is N, C, Or CR.sup.A2; at least one of X.sup.A, X.sup.B,
X.sup.C, X.sup.D, and X.sup.E is not C or CR.sup.A2; and Ring A is
a substituted or unsubstituted, 6-membered, monocyclic heteroaryl
ring. In certain embodiments, Ring A is a substituted or
unsubstituted pyridyl ring. In certain embodiments, Ring A is of
the formula:
##STR00024##
In certain embodiments, Ring A is a substituted or unsubstituted
pyrazinyl, substituted or unsubstituted pyrimidinyl, or substituted
or unsubstituted pyridazinyl ring. In certain embodiments, Ring A
is of the formula:
##STR00025##
In certain embodiments, Ring A is of the formula:
##STR00026##
In certain embodiments, Ring A is of the formula:
##STR00027##
In certain embodiments, Ring A is of the formula:
##STR00028##
[0437] In certain embodiments, at least two instances of R.sup.A1
are different from each other. In certain embodiments, all
instances of R.sup.A1 are the same. In certain embodiments, at
least one instance of R.sup.A1 is hydrogen. In certain embodiments,
each instance of R.sup.A1 is hydrogen. In certain embodiments, at
least one instance of R.sup.A1 is substituted alkyl. In certain
embodiments, at least one instance of R.sup.A1 is unsubstituted
alkyl. In certain embodiments, at least one instance of R.sup.A1 is
unsubstituted C.sub.1-6 alkyl. In certain embodiments, all
instances of R.sup.A1 are unsubstituted C.sub.1-6 alkyl. In certain
embodiments, at least one instance of R.sup.A1 is substituted
C.sub.1-6 alkyl. In certain embodiments, at least one instance of
R.sup.A1 is C.sub.1-6 alkyl substituted with at least one halogen.
In certain embodiments, at least one instance of R.sup.A1 is
--CH.sub.3. In certain embodiments, all instances of R.sup.A1 are
--CH.sub.3. In certain embodiments, at least one instance of
R.sup.A1 is substituted methyl. In certain embodiments, at least
one instance of R.sup.A1 is --CH.sub.2F, --CHF.sub.2, or
--CF.sub.3. In certain embodiments, at least one instance of
R.sup.A1 is ethyl, propyl, butyl, pentyl, or hexyl. In certain
embodiments, at least one instance of R.sup.A1 is substituted
alkenyl. In certain embodiments, at least one instance of R.sup.A1
is unsubstituted alkenyl. In certain embodiments, at least one
instance of R.sup.A1 is substituted alkynyl. In certain
embodiments, at least one instance of R.sup.A1 is unsubstituted
alkynyl. In certain embodiments, at least one instance of R.sup.A1
is substituted carbocyclyl. In certain embodiments, at least one
instance of R.sup.A1 is unsubstituted carbocyclyl. In certain
embodiments, at least one instance of R.sup.A1 is saturated
carbocyclyl. In certain embodiments, at least one instance of
R.sup.A1 is unsaturated carbocyclyl. In certain embodiments, at
least one instance of R.sup.A1 is monocyclic carbocyclyl. In
certain embodiments, at least one instance of R.sup.A1 is 3- to
7-membered, monocyclic carbocyclyl. In certain embodiments, at
least one instance of R.sup.A1 is substituted heterocyclyl. In
certain embodiments, at least one instance of R.sup.A1 is
unsubstituted heterocyclyl. In certain embodiments, at least one
instance of R.sup.A1 is saturated heterocyclyl. In certain
embodiments, at least one instance of R.sup.A1 is unsaturated
heterocyclyl. In certain embodiments, at least one instance of
R.sup.A1 is heterocyclyl, wherein one, two, or three atoms in the
heterocyclic ring system are independently selected from the group
consisting of nitrogen, oxygen, and sulfur. In certain embodiments,
at least one instance of R.sup.A1 is monocyclic heterocyclyl. In
certain embodiments, at least one instance of R.sup.A1 is 3- to
7-membered, monocyclic heterocyclyl. In certain embodiments, at
least one instance of R.sup.A1 is substituted aryl. In certain
embodiments, at least one instance of R.sup.A1 is unsubstituted
aryl. In certain embodiments, at least one instance of R.sup.A1 is
6- to 10-membered aryl. In certain embodiments, at least one
instance of R.sup.A1 is substituted phenyl. In certain embodiments,
at least one instance of R.sup.A1 is unsubstituted phenyl. In
certain embodiments, at least one instance of R.sup.A1 is
substituted heteroaryl. In certain embodiments, at least one
instance of R.sup.A1 is unsubstituted heteroaryl. In certain
embodiments, at least one instance of R.sup.A1 is heteroaryl,
wherein one, two, three, or four atoms in the heteroaryl ring
system are independently selected from the group consisting of
nitrogen, oxygen, and sulfur. In certain embodiments, at least one
instance of R.sup.A1 is monocyclic heteroaryl. In certain
embodiments, at least one instance of R.sup.A1 is 5-membered,
monocyclic heteroaryl. In certain embodiments, at least one
instance of R.sup.A1 is 6-membered, monocyclic heteroaryl. In
certain embodiments, at least one instance of R.sup.A1 is bicyclic
heteroaryl, wherein the point of attachment may be on any atom of
the bicyclic heteroaryl ring system, as valency permits. In certain
embodiments, at least one instance of R.sup.A1 is 9- or
10-membered, bicyclic heteroaryl. In certain embodiments, at least
one instance of R.sup.A1 is --C(.dbd.O)R.sup.a (e.g.,
--C(.dbd.O)(substituted or unsubstituted C.sub.1-6 alkyl)),
--C(.dbd.O)OR.sup.a (e.g., --C(.dbd.O)O (substituted or
unsubstituted C.sub.1-6 alkyl)), or --C(.dbd.O)N(R.sup.a).sub.2
(e.g., --C(.dbd.O)NH.sub.2, --C(.dbd.O)NH (substituted or
unsubstituted C.sub.1-6 alkyl), or --C(.dbd.O)N (substituted or
unsubstituted C.sub.1-6 alkyl)-(substituted or unsubstituted
C.sub.1-6 alkyl)). In certain embodiments, at least one instance of
R.sup.A1 is a nitrogen protecting group. In certain embodiments, at
least one instance of R.sup.A1 is Bn, Boc, Cbz, Fmoc,
trifluoroacetyl, triphenylmethyl, acetyl, or Ts.
[0438] Each instance of R.sup.A1, R.sup.A2, R.sup.B, and R.sup.C
may independently include one or more substituents R.sup.a. In
certain embodiments, all instances of R.sup.a are the same. In
certain embodiments, at least two instances of R.sup.a are
different from each other. In certain embodiments, at least one
instance of R.sup.a is H. In certain embodiments, each instance of
R.sup.a is H. In certain embodiments, at least one instance of
R.sup.a is substituted or unsubstituted acyl (e.g., acetyl). In
certain embodiments, at least one instance of R.sup.a is
substituted or unsubstituted alkyl (e.g., substituted or
unsubstituted C.sub.1-6 alkyl). In certain embodiments, at least
one instance of R.sup.a is --CH.sub.3. In certain embodiments, at
least one instance of R.sup.a is --CF.sub.3, unsubstituted ethyl,
perfluoroethyl, unsubstituted propyl, perfluoropropyl,
unsubstituted butyl, or perfluorobutyl. In certain embodiments, at
least one instance of R.sup.a is substituted or unsubstituted
alkenyl (e.g., substituted or unsubstituted C.sub.1-6 alkenyl). In
certain embodiments, at least one instance of R.sup.a is
substituted or unsubstituted alkynyl (e.g., substituted or
unsubstituted C.sub.1-6 alkynyl). In certain embodiments, at least
one instance of R.sup.a is substituted or unsubstituted carbocyclyl
(e.g., substituted or unsubstituted, monocyclic, 3- to 7-membered
carbocyclyl). In certain embodiments, at least one instance of
R.sup.a is substituted or unsubstituted heterocyclyl (e.g.,
substituted or unsubstituted, monocyclic, 5- to 6-membered
heterocyclyl, wherein one, two, or three atoms in the heterocyclic
ring system are independently nitrogen, oxygen, or sulfur). In
certain embodiments, at least one instance of R.sup.a is
substituted or unsubstituted aryl (e.g., substituted or
unsubstituted, 6- to 10-membered aryl). In certain embodiments, at
least one instance of R.sup.a is substituted or unsubstituted
phenyl. In certain embodiments, at least one instance of R.sup.a is
substituted or unsubstituted heteroaryl (e.g., substituted or
unsubstituted, monocyclic, 5- to 6-membered heteroaryl, wherein
one, two, three, or four atoms in the heteroaryl ring system are
independently nitrogen, oxygen, or sulfur). In certain embodiments,
at least one instance of R.sup.a is a nitrogen protecting group
(e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl,
acetyl, or Ts) when attached to a nitrogen atom. In certain
embodiments, R.sup.a is an oxygen protecting group (e.g., silyl,
TBDPS, TBDMS, TIPS, TES, TMS, MOM, THP, t-Bu, Bn, allyl, acetyl,
pivaloyl, or benzoyl) when attached to an oxygen atom. In certain
embodiments, R.sup.a is a sulfur protecting group (e.g.,
acetamidomethyl, t-Bu, 3-nitro-2-pyridine sulfenyl,
2-pyridine-sulfenyl, or triphenylmethyl) when attached to a sulfur
atom. In certain embodiments, two instances of R.sup.a are joined
to form a substituted or unsubstituted heterocyclic ring (e.g.,
substituted or unsubstituted, monocyclic, 5- to 6-membered
heterocyclic ring, wherein one, two, or three atoms in the
heterocyclic ring system are independently nitrogen, oxygen, or
sulfur). In certain embodiments, two instances of R.sup.a are
joined to form a substituted or unsubstituted heteroaryl ring
(e.g., substituted or unsubstituted, monocyclic, 5- to 6-membered
heteroaryl ring, wherein one, two, three, or four atoms in the
heteroaryl ring system are independently nitrogen, oxygen, or
sulfur).
[0439] In certain embodiments, at least two instances of R.sup.A2
are different from each other. In certain embodiments, all
instances of R.sup.A2 are the same. In certain embodiments, at
least one instance of R.sup.A2 is hydrogen. In certain embodiments,
each instance of R.sup.A2 is hydrogen. In certain embodiments, at
least one instance of R.sup.A2 is halogen. In certain embodiments,
at least one instance of R.sup.A2 is F. In certain embodiments, at
least one instance of R.sup.A2 is Cl. In certain embodiments, at
least one instance of R.sup.A2 is Br. In certain embodiments, at
least one instance of R.sup.A2 is I (iodine). In certain
embodiments, at least one instance of R.sup.A2 is substituted
alkyl. In certain embodiments, at least one instance of R.sup.A2 is
unsubstituted alkyl. In certain embodiments, at least one instance
of R.sup.A2 is unsubstituted C.sub.1-6 alkyl. In certain
embodiments, all instances of R.sup.A2 are unsubstituted C.sub.1-6
alkyl. In certain embodiments, at least one instance of R.sup.A2 is
substituted C.sub.1-6 alkyl. In certain embodiments, at least one
instance of R.sup.A2 is C.sub.1-6 alkyl substituted with at least
one halogen. In certain embodiments, at least one instance of
R.sup.A2 is --CH.sub.3. In certain embodiments, all instances of
R.sup.A2 are --CH.sub.3. In certain embodiments, at least one
instance of R.sup.A2 is substituted methyl. In certain embodiments,
at least one instance of R.sup.A2 is --CH.sub.2F, --CHF.sub.2, or
--CF.sub.3. In certain embodiments, at least one instance of
R.sup.A2 is ethyl, propyl, butyl, pentyl, or hexyl. In certain
embodiments, at least one instance of R.sup.A2 is substituted
alkenyl. In certain embodiments, at least one instance of R.sup.A2
is unsubstituted alkenyl. In certain embodiments, at least one
instance of R.sup.A2 is substituted alkynyl. In certain
embodiments, at least one instance of R.sup.A2 is unsubstituted
alkynyl. In certain embodiments, at least one instance of R.sup.A2
is substituted carbocyclyl. In certain embodiments, at least one
instance of R.sup.A2 is unsubstituted carbocyclyl. In certain
embodiments, at least one instance of R.sup.A2 is saturated
carbocyclyl. In certain embodiments, at least one instance of
R.sup.A2 is unsaturated carbocyclyl. In certain embodiments, at
least one instance of R.sup.A2 is monocyclic carbocyclyl. In
certain embodiments, at least one instance of R.sup.A2 is 3- to
7-membered, monocyclic carbocyclyl. In certain embodiments, at
least one instance of R.sup.A2 is substituted heterocyclyl. In
certain embodiments, at least one instance of R.sup.A2 is
unsubstituted heterocyclyl. In certain embodiments, at least one
instance of R.sup.A2 is saturated heterocyclyl. In certain
embodiments, at least one instance of R.sup.A2 is unsaturated
heterocyclyl. In certain embodiments, at least one instance of
R.sup.A2 is heterocyclyl, wherein one, two, or three atoms in the
heterocyclic ring system are independently selected from the group
consisting of nitrogen, oxygen, and sulfur. In certain embodiments,
at least one instance of R.sup.A2 is monocyclic heterocyclyl. In
certain embodiments, at least one instance of R.sup.A2 is 3- to
7-membered, monocyclic heterocyclyl. In certain embodiments, at
least one instance of R.sup.A2 is substituted aryl. In certain
embodiments, at least one instance of R.sup.A2 is unsubstituted
aryl. In certain embodiments, at least one instance of R.sup.A2 is
6- to 10-membered aryl. In certain embodiments, at least one
instance of R.sup.A2 is substituted phenyl. In certain embodiments,
at least one instance of R.sup.A2 is unsubstituted phenyl. In
certain embodiments, at least one instance of R.sup.A2 is
substituted heteroaryl. In certain embodiments, at least one
instance of R.sup.A2 is unsubstituted heteroaryl. In certain
embodiments, at least one instance of R.sup.A2 is heteroaryl,
wherein one, two, three, or four atoms in the heteroaryl ring
system are independently selected from the group consisting of
nitrogen, oxygen, and sulfur. In certain embodiments, at least one
instance of R.sup.A2 is monocyclic heteroaryl. In certain
embodiments, at least one instance of R.sup.A2 is 5-membered,
monocyclic heteroaryl. In certain embodiments, at least one
instance of R.sup.A2 is 6-membered, monocyclic heteroaryl. In
certain embodiments, at least one instance of R.sup.A2 is bicyclic
heteroaryl, wherein the point of attachment may be on any atom of
the bicyclic heteroaryl ring system, as valency permits. In certain
embodiments, at least one instance of R.sup.A2 is 9- or
10-membered, bicyclic heteroaryl. In certain embodiments, at least
one instance of R.sup.A2 is --OR.sup.a. In certain embodiments, at
least one instance of R.sup.A2 is --OH. In certain embodiments, at
least one instance of R.sup.A2 is --O(substituted or unsubstituted
C.sub.1-6 alkyl). In certain embodiments, at least one instance of
R.sup.A2 is --OMe. In certain embodiments, at least one instance of
R.sup.A2 is --OEt, --OPr, or --OBu. In certain embodiments, at
least one instance of R.sup.A2 is --OBn or --OPh. In certain
embodiments, at least one instance of R.sup.A2 is --SR.sup.a. In
certain embodiments, at least one instance of R.sup.A2 is --SH. In
certain embodiments, at least one instance of R.sup.A2 is --SMe. In
certain embodiments, at least one instance of R.sup.A2 is
--N(R.sup.a).sub.2. In certain embodiments, at least one instance
of R.sup.A2 is --NH.sub.2. In certain embodiments, at least one
instance of R.sup.A2 is --NHMe. In certain embodiments, at least
one instance of R.sup.A2 is --NMe.sub.2. In certain embodiments, at
least one instance of R.sup.A2 is --CN. In certain embodiments, at
least one instance of R.sup.A2 is --SCN. In certain embodiments, at
least one instance of R.sup.A2 is --C(.dbd.NR.sup.a)R.sup.a,
--C(.dbd.NR.sup.a)OR.sup.a, or --C(.dbd.NR.sup.a)N(R.sup.a).sub.2.
In certain embodiments, at least one instance of R.sup.A2 is
--C(.dbd.O)R.sup.a or --C(.dbd.O)OR.sup.a. In certain embodiments,
at least one instance of R.sup.A2 is --C(.dbd.O)N(R.sup.a).sub.2.
In certain embodiments, at least one instance of R.sup.A2 is
--C(.dbd.O)NMe.sub.2, --C(.dbd.O)NHMe, or --C(.dbd.O)NH.sub.2. In
certain embodiments, at least one instance of R.sup.A2 is
--NO.sub.2. In certain embodiments, at least one instance of
R.sup.A2 is --NR.sup.aC(.dbd.O)R.sup.a,
--NR.sup.aC(.dbd.O)OR.sup.a, or
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2. In certain embodiments, at
least one instance of R.sup.A is --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2.
[0440] Formula (A) or (B) includes as Ring B a pyridyl ring that is
unsubstituted (e.g., when m is 0) or substituted with one or more
substituents R.sup.B (e.g., when m is 1, 2, 3, or 4). In certain
embodiments, Ring B is of the formula:
##STR00029##
In certain embodiments, Ring B is of the formula:
##STR00030##
In certain embodiments, Ring B is of the formula:
##STR00031##
In certain embodiments, Ring B is of the formula:
##STR00032##
In certain embodiments, Ring B is of the formula:
##STR00033##
In certain embodiments, Ring B is of the formula:
##STR00034##
In certain embodiments, Ring B is of the formula:
##STR00035##
In certain embodiments, Ring B is of the formula:
##STR00036##
[0441] In certain embodiments, at least two instances of R.sup.B
are different from each other. In certain embodiments, all
instances of R.sup.B are the same. In certain embodiments, at least
one instance of R.sup.B is halogen. In certain embodiments, at
least one instance of R.sup.B is F. In certain embodiments, at
least one instance of R.sup.B is Cl. In certain embodiments, at
least one instance of R.sup.B is Br. In certain embodiments, at
least one instance of R.sup.B is I (iodine). In certain
embodiments, at least one instance of R.sup.B is substituted alkyl.
In certain embodiments, at least one instance of R.sup.B is
unsubstituted alkyl. In certain embodiments, at least one instance
of R.sup.B is unsubstituted C.sub.1-6 alkyl. In certain
embodiments, all instances of R.sup.B are unsubstituted C.sub.1-6
alkyl. In certain embodiments, at least one instance of R.sup.B is
substituted C.sub.1-6 alkyl. In certain embodiments, at least one
instance of R.sup.B is C.sub.1-6 alkyl substituted with at least
one halogen. In certain embodiments, at least one instance of
R.sup.B is --CH.sub.3. In certain embodiments, all instances of
R.sup.B are --CH.sub.3. In certain embodiments, at least one
instance of R.sup.B is substituted methyl. In certain embodiments,
at least one instance of R.sup.B is --CH.sub.2F, --CHF.sub.2, or
--CF.sub.3. In certain embodiments, at least one instance of
R.sup.B is ethyl, propyl, butyl, pentyl, or hexyl. In certain
embodiments, at least one instance of R.sup.B is substituted
alkenyl. In certain embodiments, at least one instance of R.sup.B
is unsubstituted alkenyl. In certain embodiments, at least one
instance of R.sup.B is substituted alkynyl. In certain embodiments,
at least one instance of R.sup.B is unsubstituted alkynyl. In
certain embodiments, at least one instance of R.sup.B is
substituted carbocyclyl. In certain embodiments, at least one
instance of R.sup.B is unsubstituted carbocyclyl. In certain
embodiments, at least one instance of R.sup.B is saturated
carbocyclyl. In certain embodiments, at least one instance of
R.sup.B is unsaturated carbocyclyl. In certain embodiments, at
least one instance of R.sup.B is monocyclic carbocyclyl. In certain
embodiments, at least one instance of R.sup.B is 3- to 7-membered,
monocyclic carbocyclyl. In certain embodiments, at least one
instance of R.sup.B is substituted heterocyclyl. In certain
embodiments, at least one instance of R.sup.B is unsubstituted
heterocyclyl. In certain embodiments, at least one instance of
R.sup.B is saturated heterocyclyl. In certain embodiments, at least
one instance of R.sup.B is unsaturated heterocyclyl. In certain
embodiments, at least one instance of R.sup.B is heterocyclyl,
wherein one, two, or three atoms in the heterocyclic ring system
are independently selected from the group consisting of nitrogen,
oxygen, and sulfur. In certain embodiments, at least one instance
of R.sup.B is monocyclic heterocyclyl. In certain embodiments, at
least one instance of R.sup.B is 3- to 7-membered, monocyclic
heterocyclyl. In certain embodiments, at least one instance of
R.sup.B is substituted aryl. In certain embodiments, at least one
instance of R.sup.B is unsubstituted aryl. In certain embodiments,
at least one instance of R.sup.B is 6- to 10-membered aryl. In
certain embodiments, at least one instance of R.sup.B is
substituted phenyl. In certain embodiments, at least one instance
of R.sup.B is unsubstituted phenyl. In certain embodiments, at
least one instance of R.sup.B is substituted heteroaryl. In certain
embodiments, at least one instance of R.sup.B is unsubstituted
heteroaryl. In certain embodiments, at least one instance of
R.sup.B is heteroaryl, wherein one, two, three, or four atoms in
the heteroaryl ring system are independently selected from the
group consisting of nitrogen, oxygen, and sulfur. In certain
embodiments, at least one instance of R.sup.B is monocyclic
heteroaryl. In certain embodiments, at least one instance of
R.sup.B is 5-membered, monocyclic heteroaryl. In certain
embodiments, at least one instance of R.sup.B is 6-membered,
monocyclic heteroaryl. In certain embodiments, at least one
instance of R.sup.B is bicyclic heteroaryl, wherein the point of
attachment may be on any atom of the bicyclic heteroaryl ring
system, as valency permits. In certain embodiments, at least one
instance of R.sup.B is 9- or 10-membered, bicyclic heteroaryl. In
certain embodiments, at least one instance of R.sup.B is
--OR.sup.a. In certain embodiments, at least one instance of
R.sup.B is --OH. In certain embodiments, at least one instance of
R.sup.B is --O(substituted or unsubstituted C.sub.1-6 alkyl). In
certain embodiments, at least one instance of R.sup.B is --OMe. In
certain embodiments, at least one instance of R.sup.B is --OEt,
--OPr, or --OBu. In certain embodiments, at least one instance of
R.sup.B is --OBn or --OPh. In certain embodiments, at least one
instance of R.sup.B is --SR.sup.a. In certain embodiments, at least
one instance of R.sup.B is --SH. In certain embodiments, at least
one instance of R.sup.B is --SMe. In certain embodiments, at least
one instance of R.sup.B is --N(R.sup.a).sub.2. In certain
embodiments, at least one instance of R.sup.B is --NH.sub.2. In
certain embodiments, at least one instance of R.sup.B is --NHMe. In
certain embodiments, at least one instance of R.sup.B is
--NMe.sub.2. In certain embodiments, at least one instance of
R.sup.B is --CN. In certain embodiments, at least one instance of
R.sup.B is --SCN. In certain embodiments, at least one instance of
R.sup.B is --C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
or --C(.dbd.NR.sup.a)N(R.sup.a).sub.2. In certain embodiments, at
least one instance of R.sup.B is --C(.dbd.O)R.sup.a or
--C(.dbd.O)OR.sup.a. In certain embodiments, at least one instance
of R.sup.B is --C(.dbd.O)N(R.sup.a).sub.2. In certain embodiments,
at least one instance of R.sup.B is --C(.dbd.O)NMe.sub.2,
--C(.dbd.O)NHMe, or --C(.dbd.O)NH.sub.2. In certain embodiments, at
least one instance of R.sup.B is --NO.sub.2. In certain
embodiments, at least one instance of R.sup.B is
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a, or
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2. In certain embodiments, at
least one instance of R.sup.B is --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2.
[0442] In certain embodiments, m is 0. In certain embodiments, m is
1. In certain embodiments, m is 2. In certain embodiments, m is 3.
In certain embodiments, m is 4.
[0443] Formula (A) includes as Ring C a pyridyl ring that is
unsubstituted (e.g., when n is 0) or substituted with one or more
substituents R.sup.C (e.g., when n is 1, 2, 3, or 4). In certain
embodiments, Ring C is of the formula:
##STR00037##
In certain embodiments, Ring C is of the formula:
##STR00038##
In certain embodiments, Ring C is of the formula:
##STR00039##
In certain embodiments, Ring C is of the formula:
##STR00040##
In certain embodiments, Ring C is of the formula:
##STR00041##
In certain embodiments, Ring C is of the formula:
##STR00042##
In certain embodiments, Ring C is of the formula:
##STR00043##
[0444] In certain embodiments, at least two instances of R.sup.C
are different from each other. In certain embodiments, all
instances of R.sup.C are the same. In certain embodiments, at least
one instance of R.sup.C is halogen. In certain embodiments, at
least one instance of R.sup.C is F. In certain embodiments, at
least one instance of R.sup.C is Cl. In certain embodiments, at
least one instance of R.sup.C is Br. In certain embodiments, at
least one instance of R.sup.C is I (iodine). In certain
embodiments, at least one instance of R.sup.C is substituted alkyl.
In certain embodiments, at least one instance of R.sup.C is
unsubstituted alkyl. In certain embodiments, at least one instance
of R.sup.C is unsubstituted C.sub.1-6 alkyl. In certain
embodiments, all instances of R.sup.C are unsubstituted C.sub.1-6
alkyl. In certain embodiments, at least one instance of R.sup.C is
substituted C.sub.1-6 alkyl. In certain embodiments, at least one
instance of R.sup.C is C.sub.1-6 alkyl substituted with at least
one halogen. In certain embodiments, at least one instance of
R.sup.C is --CH.sub.3. In certain embodiments, all instances of
R.sup.C are --CH.sub.3. In certain embodiments, at least one
instance of R.sup.C is substituted methyl. In certain embodiments,
at least one instance of R.sup.C is --CH.sub.2F, --CHF.sub.2, or
--CF.sub.3. In certain embodiments, at least one instance of
R.sup.C is ethyl, propyl, butyl, pentyl, or hexyl. In certain
embodiments, at least one instance of R.sup.C is substituted
alkenyl. In certain embodiments, at least one instance of R.sup.C
is unsubstituted alkenyl. In certain embodiments, at least one
instance of R.sup.C is substituted alkynyl. In certain embodiments,
at least one instance of R.sup.C is unsubstituted alkynyl. In
certain embodiments, at least one instance of R.sup.C is
substituted carbocyclyl. In certain embodiments, at least one
instance of R.sup.C is unsubstituted carbocyclyl. In certain
embodiments, at least one instance of R.sup.C is saturated
carbocyclyl. In certain embodiments, at least one instance of
R.sup.C is unsaturated carbocyclyl. In certain embodiments, at
least one instance of R.sup.C is monocyclic carbocyclyl. In certain
embodiments, at least one instance of R.sup.C is 3- to 7-membered,
monocyclic carbocyclyl. In certain embodiments, at least one
instance of R.sup.C is substituted heterocyclyl. In certain
embodiments, at least one instance of R.sup.C is unsubstituted
heterocyclyl. In certain embodiments, at least one instance of
R.sup.C is saturated heterocyclyl. In certain embodiments, at least
one instance of R.sup.C is unsaturated heterocyclyl. In certain
embodiments, at least one instance of R.sup.C is heterocyclyl,
wherein one, two, or three atoms in the heterocyclic ring system
are independently selected from the group consisting of nitrogen,
oxygen, and sulfur. In certain embodiments, at least one instance
of R.sup.C is monocyclic heterocyclyl. In certain embodiments, at
least one instance of R.sup.C is 3- to 7-membered, monocyclic
heterocyclyl. In certain embodiments, at least one instance of
R.sup.C is substituted aryl. In certain embodiments, at least one
instance of R.sup.C is unsubstituted aryl. In certain embodiments,
at least one instance of R.sup.C is 6- to 10-membered aryl. In
certain embodiments, at least one instance of R.sup.C is
substituted phenyl. In certain embodiments, at least one instance
of R.sup.C is unsubstituted phenyl. In certain embodiments, at
least one instance of R.sup.C is substituted heteroaryl. In certain
embodiments, at least one instance of R.sup.C is unsubstituted
heteroaryl. In certain embodiments, at least one instance of
R.sup.C is heteroaryl, wherein one, two, three, or four atoms in
the heteroaryl ring system are independently selected from the
group consisting of nitrogen, oxygen, and sulfur. In certain
embodiments, at least one instance of R.sup.C is monocyclic
heteroaryl. In certain embodiments, at least one instance of
R.sup.C is 5-membered, monocyclic heteroaryl. In certain
embodiments, at least one instance of R.sup.C is 6-membered,
monocyclic heteroaryl. In certain embodiments, at least one
instance of R.sup.C is bicyclic heteroaryl, wherein the point of
attachment may be on any atom of the bicyclic heteroaryl ring
system, as valency permits. In certain embodiments, at least one
instance of R.sup.C is 9- or 10-membered, bicyclic heteroaryl. In
certain embodiments, at least one instance of R.sup.C is
--OR.sup.a. In certain embodiments, at least one instance of
R.sup.C is --OH. In certain embodiments, at least one instance of
R.sup.C is --O(substituted or unsubstituted C.sub.1-6 alkyl). In
certain embodiments, at least one instance of R.sup.C is --OMe. In
certain embodiments, at least one instance of R.sup.C is --OEt,
--OPr, or --OBu. In certain embodiments, at least one instance of
R.sup.C is --OBn or --OPh. In certain embodiments, at least one
instance of R.sup.C is --SR.sup.a. In certain embodiments, at least
one instance of R.sup.C is --SH. In certain embodiments, at least
one instance of R.sup.C is --SMe. In certain embodiments, at least
one instance of R.sup.C is --N(R.sup.a).sub.2. In certain
embodiments, at least one instance of R.sup.C is --NH.sub.2. In
certain embodiments, at least one instance of R.sup.C is --NHMe. In
certain embodiments, at least one instance of R.sup.C is
--NMe.sub.2. In certain embodiments, at least one instance of
R.sup.C is --CN. In certain embodiments, at least one instance of
R.sup.C is --SCN. In certain embodiments, at least one instance of
R.sup.C is --C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
or --C(.dbd.NR.sup.a)N(R.sup.a).sub.2. In certain embodiments, at
least one instance of R.sup.C is --C(.dbd.O)R.sup.a or
--C(.dbd.O)OR.sup.a. In certain embodiments, at least one instance
of R.sup.C is --C(.dbd.O)N(R.sup.a).sub.2. In certain embodiments,
at least one instance of R.sup.C is --C(.dbd.O)NMe.sub.2,
--C(.dbd.O)NHMe, or --C(.dbd.O)NH.sub.2. In certain embodiments, at
least one instance of R.sup.C is --NO.sub.2. In certain
embodiments, at least one instance of R.sup.C is
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a, or
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2. In certain embodiments, at
least one instance of R.sup.C is --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2.
[0445] In certain embodiments, n is 0. In certain embodiments, n is
1. In certain embodiments, n is 2. In certain embodiments, n is 3.
In certain embodiments, n is 4.
[0446] In certain embodiments, at least one instance of R.sup.B and
at least one instance of R.sup.C are different from each other. In
certain embodiments, the instance of R.sup.B at the carbon atom
labeled with w' is the same as the instance of R.sup.C at the
carbon atom labeled with w'', wherein w is 2, 3, 4, 5, or 6. In
certain embodiments, m and n are different from each other. In
certain embodiments, m and n are the same. In certain embodiments,
each of m and n is 0.
[0447] Formula (A) or (B) includes a divalent linker Z.sup.A that
directly covalently connects Ring A and Ring B. In certain
embodiments, Z.sup.A is a bond. In certain embodiments, Z.sup.A is
a substituted or unsubstituted C.sub.1-4 hydrocarbon chain,
optionally wherein one or more chain atoms are independently
replaced with --C(.dbd.O)--, --O--, --S--, --NR.sup.ZA--, --N.dbd.,
or .dbd.N--. In certain embodiments, when Z.sup.A is a substituted
or unsubstituted C.sub.1-4 hydrocarbon chain, Z.sup.A consists of a
chain, and optionally one or more hydrogen atoms and/or one or more
substituents (e.g., .dbd.O) on the chain, where any two
substituents may optionally be joined to form a ring. In certain
embodiments, Z.sup.A does not include unsaturated bonds in the
chain. In certain embodiments, Z.sup.A consists of one or two
unsaturated bonds in the chain. In certain embodiments, Z.sup.A is
a substituted (e.g., substituted with at least one instance of
halogen) C.sub.1-4 hydrocarbon chain. In certain embodiments,
Z.sup.A is an unsubstituted C.sub.1-4 hydrocarbon chain. In certain
embodiments, the molecular weight of Z.sup.A is not more than 150
g/mol, not more than 100 g/mol, not more than 80 g/mol, not more
than 50 g/mol, or not more than 30 g/mol. In certain embodiments,
Z.sup.A consists of not more than 50 atoms, not more than 40 atoms,
not more than 30 atoms, not more than 20 atoms, or not more than 10
atoms. In certain embodiments, Z.sup.A is --C.ident.C-- or
--C.ident.C--C.ident.C--. In certain embodiments, Z.sup.A is of the
formula:
##STR00044##
[0448] In certain embodiments, all instances of R.sup.ZA are the
same. In certain embodiments, at least two instances of R.sup.ZA
are different from each other. In certain embodiments, at least one
instance of R.sup.ZA is hydrogen. In certain embodiments, all
instances of R.sup.ZA are hydrogen. In certain embodiments, at
least one instance of R.sup.ZA is substituted or unsubstituted
C.sub.1-6 alkyl (e.g., --CH.sub.3, --CF.sub.3, unsubstituted ethyl,
perfluoroethyl, unsubstituted propyl, perfluoropropyl,
unsubstituted butyl, or perfluorobutyl). In certain embodiments, at
least one instance of R.sup.ZA is a nitrogen protecting group
(e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl,
acetyl, or Ts).
[0449] In certain embodiments, Z.sup.A is directly covalently
attached to the carbon atom labeled with 2' or 6' of Ring B. In
certain embodiments, Z.sup.A is directly covalently attached to the
carbon atom labeled with 3' or 5' of Ring B. In certain
embodiments, Z.sup.A is directly covalently attached to the carbon
atom labeled with 4' of Ring B.
[0450] Formula (A) includes a divalent linker Z.sup.B that directly
covalently connects Ring A and Ring C. In certain embodiments,
Z.sup.B is a bond. In certain embodiments, Z.sup.B is a substituted
or unsubstituted C.sub.1-4 hydrocarbon chain, optionally wherein
one or more chain atoms are independently replaced with
--C(.dbd.O)--, --O--, --S--, --NR.sup.ZB--, --N.dbd., or .dbd.N--.
In certain embodiments, when Z.sup.B is a substituted or
unsubstituted C.sub.1-4 hydrocarbon chain, Z.sup.B consists of a
chain, and optionally one or more hydrogen atoms and/or one or more
substituents (e.g., .dbd.O) on the chain, where any two
substituents may optionally be joined to form a ring. In certain
embodiments, Z.sup.B does not include unsaturated bonds in the
chain. In certain embodiments, Z.sup.B consists of one or two
unsaturated bonds in the chain. In certain embodiments, Z.sup.B is
a substituted (e.g., substituted with at least one instance of
halogen) C.sub.1-4 hydrocarbon chain. In certain embodiments,
Z.sup.B is an unsubstituted C.sub.1-4 hydrocarbon chain. In certain
embodiments, the molecular weight of Z.sup.B is not more than 150
g/mol, not more than 100 g/mol, not more than 80 g/mol, not more
than 50 g/mol, or not more than 30 g/mol. In certain embodiments,
Z.sup.B consists of not more than 50 atoms, not more than 40 atoms,
not more than 30 atoms, not more than 20 atoms, or not more than 10
atoms. In certain embodiments, Z.sup.B is --C.ident.C-- or
--C.ident.C--C.ident.C--. In certain embodiments, Z.sup.B is of the
formula:
##STR00045##
[0451] In certain embodiments, all instances of R.sup.ZB are the
same. In certain embodiments, at least two instances of R.sup.ZB
are different from each other. In certain embodiments, at least one
instance of R.sup.ZB is hydrogen. In certain embodiments, all
instances of R.sup.ZB are hydrogen. In certain embodiments, at
least one instance of R.sup.ZB is substituted or unsubstituted
C.sub.1-6 alkyl (e.g., --CH.sub.3, --CF.sub.3, unsubstituted ethyl,
perfluoroethyl, unsubstituted propyl, perfluoropropyl,
unsubstituted butyl, or perfluorobutyl). In certain embodiments, at
least one instance of R.sup.ZB is a nitrogen protecting group
(e.g., Bn, Boc, Cbz, Fmoc, trifluoroacetyl, triphenylmethyl,
acetyl, or Ts).
[0452] In certain embodiments, Z.sup.B is directly covalently
attached to the carbon atom labeled with 2 or 6 of Ring A. In
certain embodiments, Z.sup.B is directly covalently attached to the
carbon atom labeled with 3 or 5 of Ring A. In certain embodiments,
Z.sup.B is directly covalently attached to the carbon atom labeled
with 4 of Ring A.
[0453] In certain embodiments, Z.sup.B is directly covalently
attached to the carbon atom labeled with 2'' or 6'' of Ring C. In
certain embodiments, Z.sup.B is directly covalently attached to the
carbon atom labeled with 3'' or 5'' of Ring C. In certain
embodiments, Z.sup.B is directly covalently attached to the carbon
atom labeled with 4'' of Ring C.
[0454] In certain embodiments, Z.sup.A and Z.sup.B are different
from each other. In certain embodiments, Z.sup.A and Z.sup.B are
the same. In certain embodiments, each of Z.sup.A and Z.sup.B is a
bond.
[0455] In certain embodiments, Z.sup.A is directly covalently
attached to the carbon atom labeled with 2' or 6' of Ring B; and
Z.sup.B is directly covalently attached to the carbon atom labeled
with 2'' or 6'' of Ring C. In certain embodiments, Z.sup.A is
directly covalently attached to the carbon atom labeled with 3' or
5' of Ring B; and Z.sup.B is directly covalently attached to the
carbon atom labeled with 3'' or 5'' of Ring C. In certain
embodiments, Z.sup.A is directly covalently attached to the carbon
atom labeled with 4' of Ring B; and Z.sup.B is directly covalently
attached to the carbon atom labeled with 4'' of Ring C.
[0456] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00046##
[0457] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00047##
[0458] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00048##
[0459] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00049##
[0460] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00050##
[0461] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00051##
[0462] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00052##
[0463] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00053##
[0464] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00054##
[0465] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00055##
[0466] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00056##
[0467] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00057##
[0468] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00058##
[0469] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00059##
[0470] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00060##
[0471] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00061##
[0472] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00062##
[0473] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00063##
[0474] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00064##
[0475] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00065##
[0476] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00066##
[0477] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00067##
[0478] In certain embodiments, the ligand of Formula (A) is of the
formula:
##STR00068##
[0479] In certain embodiments, at least one instance of the ligand
of Formula (B) is of the formula:
##STR00069## ##STR00070## ##STR00071## ##STR00072##
##STR00073##
[0480] In certain embodiments, each instance of the ligand of
Formula (A) or (B) forms through coordination bonds a coordination
complex with one instance of the transition metal ion. In certain
embodiments, an instance of the coordination bonds is formed
between an instance of the transition metal ion and the nitrogen
atom labeled with 1' of an instance of the ligand of Formula (A) or
(B). In certain embodiments, an instance of the coordination bonds
is formed between an instance of the transition metal ion and the
nitrogen atom labeled with 1'' of an instance of the ligand of
Formula (A) or (B). In certain embodiments, an instance of the
coordination bonds is formed between an instance of the transition
metal ion and the nitrogen atom labeled with 1' of an instance of
the ligand of Formula (A) or (B), and another instance of the
coordination bonds is formed between the instance of the transition
metal ion and the nitrogen atom labeled with 1'' of the instance of
the ligand of Formula (A) or (B).
[0481] In certain embodiments, at least one instance of the
transition metal ion and at least two instances of the ligand of
Formula (C) form through two or more coordination bonds
coordination complex(es). In certain embodiments, at least 30%, at
least 40%, at least 50%, at least 60%, at least 70%, or at least
80% of all instances of the oxygen atom labeled with "*" of a
ligand of Formula (C) form coordination bonds with one or more
instances of the transition metal ion.
[0482] In certain embodiments, at least one instance of the metal
organic nanostructure (e.g., coordination complex) is in a square
planar molecular geometry. In certain embodiments, at least one
instance of the metal organic nanostructure (e.g., coordination
complex) is in a pseudo square planar molecular geometry. The metal
organic nanostructure may be a nanosphere. In certain embodiments,
the metal organic nanostructure has cuboctahedral symmetry. In
certain embodiments, the metal organic nanostructure has
quasi-regular polyhedral symmetry, icosidodecahedral symmetry, or
regular polyhedral symmetry (e.g., cubic (regular hexahedral) or
dodecahedral symmetry). In certain embodiments, the metal organic
nanostructure is a nano-paddlewheel. In certain embodiments, the
metal organic nanostructure is a nano-square.
[0483] A metal organic nanostructure described herein is hollow
(e.g., including a cavity). In certain embodiments, the maximum
outer dimension (e.g., diameter) of a metal organic nanostructure
described herein is not more than 100 nm, not more than 60 nm, not
more than 30 nm, not more than 10 nm, not more than 5 nm, not more
than 3 nm, or not more than 1 nm. In certain embodiments, the
maximum outer dimension of the a metal organic nanostructure
described herein is at least 1 nm, at least 2 nm, at least 5 nm, at
least 10 nm, at least 30 nm, at least 60 nm, or at least 100 nm.
Combinations of the above ranges (e.g., at least 1 nm and not more
than 100 nm or at least 1 nm and not more than 10 nm) are also
within the scope of the present disclosure. The minimum inner
dimension (e.g., diameter) of a metal organic nanostructure
described herein is the minimum dimension of the cavity of the
nanostructure. In certain embodiments, the minimum inner dimension
of a metal organic nanostructure described herein is not more than
100 nm, not more than 60 nm, not more than 30 nm, not more than 10
nm, not more than 5 nm, not more than 3 nm, or not more than 1 nm.
In certain embodiments, the minimum inner dimension of the
nanostructure described herein is at least 1 nm, at least 2 nm, at
least 5 nm, at least 10 nm, at least 30 nm, at least 60 nm, or at
least 100 nm. Combinations of the above ranges (e.g., at least 1 nm
and not more than 60 nm or at least 1 nm and not more than 5 nm)
are also within the scope of the present disclosure.
[0484] In certain embodiments, a metal organic nanostructure
described herein is not a polymer or does not include a polymeric
moiety.
[0485] In certain embodiments, a nanosphere described herein is of
Formula (I-A) as shown in FIG. 40, or a salt thereof, wherein each
instance of the black dots is the transition metal ion; each
instance of the grey lines is the ligand of Formula (A); and each
instance of the black lines is the coordination bond. In certain
embodiments, a nanosphere described herein is of Formula (I-B) as
shown in FIG. 41, or a salt thereof, wherein each instance of the
black dots is the transition metal ion; and each instance of the
grey lines is the ligand of Formula (A). In certain embodiments, a
nano-paddlewheel described herein is of Formula (I-C) as shown in
FIG. 42, or a salt thereof, wherein each instance of the dots is
the transition metal ion; and each instance of the U-shaped lines
is the ligand of Formula (A). In certain embodiments, a nano-square
described herein is of Formula (II-A) as shown in the second view
of FIG. 1C, or a salt thereof, the dot is the transition metal ion;
and each instance of the lines is the ligand of Formula (B). In
certain embodiments, a nanosphere described herein (nanosphere I-1)
is of Formula (I-A), wherein each instance of is ligand A-1. In
Formula (I-A), each instance of the moiety
is of the formula:
##STR00074##
[0486] In certain embodiments, each instance of the moiety
is of the formula:
##STR00075##
[0487] In certain embodiments, each instance of the metal organic
nanostructure is the same. In certain embodiments, two or more
instances of the metal organic nanostructure are different from
each other. In certain embodiments, the variables x of all
instances of the metal organic nanostructure are the same. In
certain embodiments, the variables x of two or more instances of
the metal organic nanostructure are different from each other. In
certain embodiments, each instance of the ligand of Formula (A) is
the same. In certain embodiments, two or more instances of the
ligand of Formula (A) are different from each other. In certain
embodiments, each instance of the ligand of Formula (B) is the
same. In certain embodiments, two or more instances of the ligand
of Formula (B) are different from each other.
[0488] In certain embodiments, a BCPMON described herein also
includes two or more instances of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E. In certain
embodiments, all instances of -L-(R).sub.p-(G)q
(R).sub.u-(G).sub.v-E are the same. In certain embodiments, at
least two instances of -L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E
are different from each other. In certain embodiments, at least one
instance of L is a bond. In certain embodiments, each instance of L
is a bond. In certain embodiments, at least one instance of L is
substituted or unsubstituted C.sub.1-4 hydrocarbon chain. In
certain embodiments, at least one instance of L is substituted or
unsubstituted C.sub.1-4 hydrocarbon chain, wherein one or more
chain atoms are independently replaced with --C(.dbd.O)--, --O--,
--S--, --NR.sup.L--, --N.dbd., or .dbd.N--. In certain embodiments,
at least one instance of L is --O--.
[0489] In certain embodiments, all instances of R.sup.L are the
same. In certain embodiments, at least two instances of R.sup.L are
different from each other. In certain embodiments, at least one
instance of R.sup.L is hydrogen. In certain embodiments, each
instance of R.sup.L is hydrogen. In certain embodiments, at least
one instance of R.sup.L is substituted or unsubstituted C.sub.1-6
alkyl or a nitrogen protecting group. In certain embodiments, at
least one instance of R.sup.L is C.sub.1-6 alkyl substituted with
at least one halogen. In certain embodiments, at least one instance
of R.sup.L is --CH.sub.3. In certain embodiments, all instances of
R.sup.L are --CH.sub.3. In certain embodiments, at least one
instance of R.sup.L is substituted methyl. In certain embodiments,
at least one instance of R.sup.L is --CH.sub.2F, --CHF.sub.2, or
--CF.sub.3. In certain embodiments, at least one instance of
R.sup.L is Et, Pr, Bu, unsubstituted pentyl, or unsubstituted
hexyl. In certain embodiments, at least one instance of R.sup.L is
a nitrogen protecting group (e.g., Bn, Boc, Cbz, Fmoc,
trifluoroacetyl, triphenylmethyl, acetyl, or Ts).
[0490] In certain embodiments, all instances of R are the same. In
certain embodiments, at least two instances of R are different from
each other. In certain embodiments, the glass transition
temperature (T.sub.g) of each instance of the first polymer is not
higher than 20.degree. C. (e.g., not higher than 10.degree. C., not
higher than 0.degree. C., not higher than -10.degree. C., not
higher than -20.degree. C., not higher than -40.degree. C., or not
higher than -60.degree. C.).
[0491] In certain embodiments, at least one instance of the first
polymer is a poly(alkyl acrylate), a poly(hydroxyalkyl acrylate),
poly(haloalkyl acrylate), polymethacrylate, a poly(alkyl
methacrylate), a poly(hydroxyalkyl methacrylate), or a
poly(haloalkyl methacrylate). In certain embodiments, at least one
instance of the first polymer is poly(n-butyl acrylate) (PBA). In
certain embodiments, at least one instance of the first polymer is
polydimethylsiloxane, polybutadiene, or polyisoprene. In certain
embodiments, each instance of the first polymer has the same
repeating unit. In certain embodiments, at least two instances of
the first polymer have different repeating units.
[0492] In certain embodiments, the number-average molecular weight
(M) of the first polymer is between 1,000 g/mol and 1,000,000
g/mol, inclusive (e.g., between 3,000 g/mol and 300,000 g/mol,
between 3,000 g/mol and 100,000 g/mol, between 10,000 g/mol and
300,000 g/mol, or between 10,000 g/mol and 100,000 g/mol).
[0493] In certain embodiments, all instances of G are the same. In
certain embodiments, at least two instances of G are different from
each other. In certain embodiments, the T.sub.g of each instance of
the second polymer is higher than 20.degree. C. (e.g., higher than
40.degree. C., higher than 60.degree. C., higher than 80.degree.
C., higher than 100.degree. C., higher than 120.degree. C., higher
than 140.degree. C., higher than 160.degree. C., or higher than 180
OC).
[0494] In certain embodiments, the M.sub.n of the second polymer is
between 300 g/mol and 100,000 g/mol, inclusive (e.g., between 1,000
g/mol and 30,000 g/mol, between 1,000 g/mol and 10,000 g/mol,
between 3,000 g/mol and 30,000 g/mol, or between 3,000 g/mol and
10,000 g/mol, inclusive).
[0495] In certain embodiments, at least one instance of the second
polymer is a poly(alkyl acrylate), a poly(hydroxyalkyl acrylate),
poly(haloalkyl acrylate), polymethacrylate, a poly(alkyl
methacrylate), a poly(hydroxyalkyl methacrylate), or a
poly(haloalkyl methacrylate). In certain embodiments, at least one
instance of the second polymer is poly(methyl methacrylate) (PMMA).
In certain embodiments, at least one instance of the second polymer
is polystyrene or polyethylene.
[0496] In certain embodiments, at least one instance of the first
polymer or second polymer is an addition polymer (e.g.,
polyethylene, poly(tetrafluoroethylene), polypropylene,
polyisobutylene, polystyrene, polyacrylonitrile, poly(vinyl
chloride), poly(methyl acrylate), poly(methyl methacrylate),
polybutadiene, polychloroprene, poly(cis-1,4-isoprene), or
poly(trans-1,4-isoprene)). In certain embodiments, at least one
instance of the first polymer or second polymer is an condensation
polymer (e.g., polyamide, polyaramide, polyester, polycarbonate, or
silicone). In certain embodiments, at least one instance (e.g.,
each instance) of the first polymer is different from at least one
instance (e.g., each instance) of the second polymer.
[0497] In certain embodiments, at least one instance of the second
polymer is a semi-crystalline polymer (e.g., a semi-crystalline
polymer under ambient conditions) whose melting temperature (e.g.,
melting temperature under 1 atmosphere) is higher than 20.degree.
C. (e.g., higher than 40, higher than 60, higher than 80, higher
than 100, higher than 150, higher than 200, or higher than
300.degree. C.). In certain embodiments, each instance of the
second polymer has the same repeating unit. In certain embodiments,
at least two instances of the second polymer have different
repeating units.
[0498] In some embodiments, the polydispersity of the polymer
(e.g., first polymer or second polymer) is less than about 0.5
(e.g., less than about 0.4, about 0.35, about 0.3, about 0.25,
about 0.2, about 0.15, or less). In some embodiments, the
polydispersity of the polymer is less than about 0.3. In some
embodiments, the polydispersity of the polymer is less than about
0.2. In some embodiments, the polymer is monodisperse. In some
embodiments, the polymer is about 50% monodisperse (e.g., about
55%, about 60%, about 65%, about 70%, about 75%, about 80%, about
85%, about 90%, about 95%, about 99%, or about 99.9%
monodisperse).
[0499] In certain embodiments, ratio of the M.sub.n of the first
polymer to the M.sub.n of the second polymer is between 100:1 and
1:1, between 30:1 and 1:1, between 10:1 and 1:1, between 3:1 and
1:1, between 100:1 and 3:1, between 30:1 and 3:1, between 10:1 and
3:1, between 100:1 and 10:1, or between 30:1 and 10:1,
inclusive.
[0500] In certain embodiments, at least one instance of p is 1, 2,
or 3. In certain embodiments, each instance of p is 1.
[0501] In certain embodiments, at least one instance of q is 1, 2,
or 3. In certain embodiments, each instance of q is 1.
[0502] In certain embodiments, each instance of p is 1, and each
instance of q is 0. In certain embodiments, each instance of p is
0, and each instance of q is 1.
[0503] In certain embodiments, at least one instance of u is 1, 2,
or 3. In certain embodiments, each instance of u is 0.
[0504] In certain embodiments, at least one instance of v is 1, 2,
or 3. In certain embodiments, each instance of v is 0.
[0505] In certain embodiments, each instance of E is the same. In
certain embodiments, at least two instances of E are different from
each other. In certain embodiments, at least one instance of E is
hydrogen. In certain embodiments, each instance of E is hydrogen.
In certain embodiments, at least one instance of E is hydrogen or
substituted or unsubstituted C.sub.1-6 alkyl. In certain
embodiments, at least one instance of E is substituted or
unsubstituted alkyl, substituted or unsubstituted alkenyl, or
substituted or unsubstituted alkynyl. In certain embodiments, at
least one instance of E is substituted or unsubstituted
carbocyclyl, substituted or unsubstituted heterocyclyl, substituted
or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
In certain embodiments, at least one instance of E is --OR.sup.a,
--N(R.sup.a).sub.2, --SR.sup.a, --CN, --SCN,
--C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2.
[0506] In certain embodiments, no two or more instances of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E are directly
covalently attached to the same instance of the ligand of Formula
(A) or (B). In certain embodiments, at least one instance (e.g.,
each instance) of -L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E is
directly covalently attached to the 5-position of an instance of
the ligand of Formula (A) or (B). In certain embodiments, at least
one instance (e.g., each instance) of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E is directly covalently
attached to the 4-position of an instance of the ligand of Formula
(A) or (B). In certain embodiments, each instance of the ligand of
Formula (A) or (B) is directly covalently attached to one instance
of -L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E.
[0507] In certain embodiments, at least one instance of the
coordination complex is substantively of a framework described in
U.S. patent application publication, US 2003/0004364, which is
incorporated herein by reference. In certain embodiments, at least
one instance (e.g., each instance) of the coordination complex is
substantively of the MOF-5 framework as shown in FIG. 43.
[0508] In certain embodiments, the BCPMON further comprises:
[0509] a first phase, wherein the first phase comprises more than
50% (e.g., more than 60%, more than 70%, more than 80%, or more
than 90%) of all instances of the coordination complexes;
[0510] a second phase, wherein the second phase comprises more than
50% (e.g., more than 60%, more than 70%, more than 80%, or more
than 90%) of all instances of
--(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E; and
[0511] optionally a third phase;
[0512] wherein, compared to the second phase, the first phase is
the inner phase of the BCPMON and is more crystalline under ambient
conditions.
[0513] In certain embodiments, the first phase is crystalline under
ambient conditions. In certain embodiments, the first phase is
semi-crystalline under ambient conditions. In certain embodiments,
the second phase is semi-crystalline or not crystalline, under
ambient conditions. In certain embodiments, the second phase is
amorphous under ambient conditions.
[0514] In certain embodiments, the maximum outer dimension of the
first phase is between 1 nm and 1,000 nm, between 1 nm and 100 nm,
between 1 nm and 10 nm, between 10 nm and 1,000 nm, between 10 nm
and 100 nm, or between 100 nm and 1,000 nm, inclusive. In certain
embodiments, the maximum outer dimension of the first phase is
between 1 nm and 100 nm, inclusive.
[0515] In certain embodiments, y is an integer between 1 and 100,
between 1 and 10, between 10 and 1,000, between 10 and 100, or
between 100 and 1,000, inclusive. In certain embodiments, y is an
integer between 10 and 100, inclusive.
[0516] In certain embodiments, z is an integer between 2 and 50,
between 2 and 10, between 10 and 200, between 10 and 50, or between
50 and 200, inclusive. In certain embodiments, z is an integer
between 2 and 20, inclusive.
[0517] In certain embodiments, s is 2. In certain embodiments, s is
an integer between 3 and 10, inclusive. In certain embodiments, s
is 3, 4, or 5. In certain embodiments, s is 4.
[0518] In certain embodiments, each instance of R.sup.D is the
same. In certain embodiments, at least two instances of R.sup.D are
different from each other. In certain embodiments, at least one
instance of R.sup.D is hydrogen. In certain embodiments, each
instance of R.sup.D is hydrogen. In certain embodiments, at least
one instance of R.sup.D is halogen. In certain embodiments, at
least one instance of R.sup.D is substituted or unsubstituted
C.sub.1-6 alkyl (e.g., Me). In certain embodiments, at least one
instance of R.sup.D is --OR.sup.a, --N(R.sup.a).sub.2, --SR.sup.a,
--CN, --SCN, --C(.dbd.NR.sup.a)R.sup.a, --C(.dbd.NR.sup.a)OR.sup.a,
--C(.dbd.NR.sup.a)N(R.sup.a).sub.2, --C(.dbd.O)R.sup.a,
--C(.dbd.O)OR.sup.a, --C(.dbd.O)N(R.sup.a).sub.2, --NO.sub.2,
--NR.sup.aC(.dbd.O)R.sup.a, --NR.sup.aC(.dbd.O)OR.sup.a,
--NR.sup.aC(.dbd.O)N(R.sup.a).sub.2, --OC(.dbd.O)R.sup.a,
--OC(.dbd.O)OR.sup.a, or --OC(.dbd.O)N(R.sup.a).sub.2.
[0519] In certain embodiments, each instance of T is the same. In
certain embodiments, at least two instances of T are different from
each other. In certain embodiments, at least one instance of T is a
bond. In certain embodiments, at least one instance of (e.g., each
instance) of T is independently a substituted or unsubstituted
C.sub.1-50 hydrocarbon chain, wherein one or more (e.g., 2) chain
atoms are independently replaced with --C(.dbd.O)--, --O--, --S--,
--NR.sup.T--, --N.dbd., or .dbd.N--. In certain embodiments, at
least one instance of (e.g., each instance) of T is independently a
substituted or unsubstituted C.sub.5-20 hydrocarbon chain, wherein
one or more (e.g., 2) chain atoms are independently replaced with
--C(.dbd.O)--, --O--, --S--, or --NR.sup.T--. In certain
embodiments, at least one instance of (e.g., each instance) of T is
independently --O--(CH.sub.2).sub.t--O--, wherein t is an integer
between 4 and 16, inclusive.
[0520] In certain embodiments, W is substituted or unsubstituted,
C.sub.2-200 alkynylene. In certain embodiments, W is substituted or
unsubstituted, C.sub.2-200 heteroalkynylene. In certain
embodiments, W is substituted or unsubstituted, C.sub.2-200
heteroalkylene, wherein one or more carbons and/or one or more
heteroatoms, of the substituted or unsubstituted, C.sub.2-200
heteroalkylene, are independently replaced with substituted or
unsubstituted heteroarylene. In certain embodiments, W is
substituted or unsubstituted, C.sub.2-200 heteroalkylene, wherein
one or more carbons and/or one or more heteroatoms, of the
substituted or unsubstituted, C.sub.2-200 heteroalkylene, are
independently replaced with
##STR00076##
wherein --(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E is closer to
the attachment point labeled with "***" than the attachment point
labeled with "**". In certain embodiments, W is substituted or
unsubstituted, C.sub.2-200 heteroalkylene, wherein one carbon or
one heteroatom, of the substituted or unsubstituted, C.sub.2-200
heteroalkylene, is replaced with
##STR00077##
wherein --(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E is closer to
the attachment point labeled with "***" than the attachment point
labeled with "**"
[0521] In certain embodiments, W comprises
##STR00078##
wherein:
[0522] each instance of k is independently an integer from 1 to 10,
inclusive;
[0523] each instance of L.sup.F is independently substituted or
unsubstituted, C.sub.2-180 heteroalkylene;
[0524] each instance of -L.sup.B-L.sup.A- is independently
--C(.dbd.O)O--, --OC(.dbd.O)--, --C(.dbd.O)NR.sup.E--, or
--NR.sup.EC(.dbd.O)--, wherein each instance of R.sup.E is
independently hydrogen, substituted or unsubstituted, C.sub.1-6
alkyl, or a nitrogen protecting group; and
[0525] --(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E is closer to the
attachment point labeled with "***" than the attachment point
labeled with "**"
[0526] In certain embodiments, W is
##STR00079##
[0527] In certain embodiments, W comprises
##STR00080##
wherein:
[0528] each instance of k is independently an integer from 1 to 10,
inclusive;
[0529] each instance of L.sup.C is independently substituted or
unsubstituted, C.sub.1-180 alkylene;
[0530] each instance of -L.sup.B-L.sup.A- is independently
--C(.dbd.O)O--, --OC(.dbd.O)--, --C(.dbd.O)NR.sup.E--, or
--NR.sup.EC(.dbd.O)--, wherein each instance of R.sup.E is
independently hydrogen, substituted or unsubstituted, C.sub.1-6
alkyl, or a nitrogen protecting group; and
[0531] --(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E is closer to the
attachment point labeled with "***" than the attachment point
labeled with "**"
[0532] In certain embodiments, W is
##STR00081##
In certain embodiments, each instance of L is independently
C.sub.1-180 alkylene substituted with one or more instances of:
substituted or unsubstituted phenyl and/or substituted or
unsubstituted, C.sub.1-6 alkyl.
[0533] In certain embodiments, W comprises a polymer (e.g.,
substituted or unsubstituted polyethylene (e.g., unsubstituted
polystyrene), optionally wherein the M.sub.n of the polymer is
between 300 and 10,000, between 300 and 3,000, between 300 and
1,000, between 1,000 and 10,000, between 1,000 and 3,000, or
between 3,000 and 10,000, inclusive, g/mol.
[0534] In certain embodiments, W comprises a natural amino acid, an
unnatural amino acid, or a peptide, optionally wherein the peptide
consists of between 3 and 60, between 3 and 30, between 3 and 10,
between 10 and 60, between 10 and 30, or between 30 and 60,
inclusive, amino acids.
[0535] In certain embodiments, W is cleavable by ultraviolet
irradiation. In certain embodiments, W is cleavable by hydrolysis,
reduction, or oxidation. In certain embodiments, W is cleavable by
contacting with an enzyme. In certain embodiments, at least 50% of
all instances of W that is cleavable is cleaved after 10 minutes, 1
hour, 6 hours, 12 hours, 1 day, 2 days, 3 days, 5 days, or 7 days
of the ultraviolet irradiation, hydrolysis, reduction, oxidation,
or contact with the enzyme. In certain embodiments, W is stable
(e.g., having a half life of at least 1 day, 3 days, 7 days, 1
month, 3 months, 6 months, or 1 year) under ambient conditions.
[0536] In certain embodiments, r is 1. In certain embodiments, r is
2 or 3.
[0537] In certain embodiments, the macromonomer is a ligand of
Formula (A)
##STR00082##
covalently attached to r instances of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E. In certain
embodiments, the macromonomer is a ligand of Formula (B)
##STR00083##
covalently attached to r instances of
-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E. In certain
embodiments, r instances of hydrogen atom are removed from a ligand
of Formula (A) or (B) to form the attachment points.
[0538] In certain embodiments, the macromonomer is of the
formula:
##STR00084##
[0539] In certain embodiments, the macromonomer is of the
formula:
##STR00085##
[0540] In certain embodiments, the macromonomer is of the
formula:
##STR00086##
[0541] In certain embodiments, the macromonomer is of the
formula:
##STR00087##
wherein the first polymer is poly(n-butyl acrylate) (PBA), and the
second polymer is poly(methyl methacrylate) (PMMA).
[0542] In certain embodiments, the macromonomer is of the
formula:
##STR00088##
[0543] In certain embodiments, the macromonomer is of the
formula:
##STR00089##
wherein the first polymer is poly(n-butyl acrylate) (PBA), and the
second polymer is poly(methyl methacrylate) (PMMA).
[0544] In certain embodiments, the macromonomer is of the
formula:
##STR00090##
[0545] In certain embodiments, the macromonomer is of the
formula:
##STR00091##
[0546] In certain embodiments, the macromonomer is of the
formula:
##STR00092##
[0547] In certain embodiments, the macromonomer is of the
formula:
##STR00093##
wherein the first polymer is poly(n-butyl acrylate) (PBA), and the
second polymer is poly(methyl methacrylate) (PMMA).
[0548] In certain embodiments, the BCPMON further comprises at
least one instance of an anionic counterion. The anionic
counterions may reduce the overall electric charge of the BCPMON,
each of which includes transition metal ions that are positively
charged. In certain embodiments, at least two instances of the
anionic counterion are different. In certain embodiments, all
instances of the anionic counterion are the same. In certain
embodiments, the BCPMON is substantially electrically neutral. In
certain embodiments, the BCPMON is slightly positively charged. In
certain embodiments, the .zeta.-potential of the BCPMON is between
about 0 and about +30 mV, inclusive (e.g., between about 0 and
about 10 mV, inclusive). In certain embodiments, the BCPMON is
slightly negatively charged. In certain embodiments, the
c-potential of the BCPMON is between about -30 and about 0 mV,
inclusive (e.g., between about -10 and about 0 mV, inclusive). In
certain embodiments, at least one instance of the anionic
counterion is a non-coordinating anionic counterion (e.g.,
ClO.sub.4.sup.-, NO.sub.3.sup.-, TfO.sup.-, BF.sub.4.sup.-,
PF.sub.4.sup.-, PF.sub.6.sup.-, AsF.sub.6.sup.-, or
SbF.sub.6.sup.-). In certain embodiments, at least one instance
(e.g., each instance) of the anionic counterion is NO.sub.3.sup.-.
In certain embodiments, at least one instance of the anionic
counterion is AcO.sup.-, F.sup.-, Cl.sup.-, Br.sup.-, or I.sup.-.
In certain embodiments, at least one instance of the anionic
counterion is a coordinating anionic counterion. In certain
embodiments, at least one instance (e.g., each instance) of the
anionic counterion is at the outer surface of at least one instance
of the BCPMON. In certain embodiments, at least one instance of the
anionic counterion is encapsulated by at least one instance of the
BCPMON.
Thermoplastic Elastomers
[0549] Another aspect of the present disclosure relates to
thermoplastic elastomers comprising two or more instances of a
BCPMON described herein.
[0550] Thermoplastic elastomers, such as styrene-butadiene block
copolymers, thermoplastic polyurethanes, polyester amides,
polyether amides, thermoplastic copolyester elastomers and
polyolefin alloys with elastomers, are known (Rader, C.,
Kunststoffe 83 (1993) 10, 777-781, Kunststoffe 86, (1996) 12,
1845-1851). The thermoplastic elastomers described herein may be
advantageous over known thermoplastic elastomers in that one or
more of the properties (e.g., tensile modulus, tensile strength,
tensile elongation, nominal tensile strain at break, flexural
modulus, flexural stress, taber abrasion resistance, tensile set,
tensile stress, tear strength, compression set, hardness,
deflection temperature under load, continuous use temperature,
brittleness temperature, Vicat softening temperature, RTI Elec, RTI
Str, change in volume) are tunable (e.g., by changing the framework
type of the MOFs) and/or reversible (e.g., by subjecting the
BCPMONs to different conditions). In certain embodiments, each
instance of the ligand of Formula (A) is the same. In certain
embodiments, two or more instances of the ligand of Formula (A) are
different from each other. In certain embodiments, each instance of
the ligand of Formula (B) is the same. In certain embodiments, two
or more instances of the ligand of Formula (B) are different from
each other. In certain embodiments, each instance of the transition
metal ion or transition metal salt is the same. In certain
embodiments, two or more instances of the transition metal ion or
transition metal salt are different from each other.
Compositions
[0551] In another aspect, the present disclosure provides
compositions comprising a MON described herein and optionally an
excipient. A composition described herein may further comprise a
solvent (e.g., a suitable solvent described herein, such as water
or DMSO). The solvent may be encapsulated inside a MON and/or be
present outside of any MON in the composition.
[0552] In still another aspect, the present disclosure provides
compositions comprising a BCPMON described herein and optionally an
excipient. In another aspect, the present disclosure provides
compositions comprising a thermoplastic elastomer described herein
and optionally an excipient. In another aspect, the present
disclosure provides compositions comprising a macromonomer
described herein and optionally an excipient.
[0553] The excipient included in a composition described herein may
be a pharmaceutically acceptable excipient, cosmetically acceptable
excipient, dietarily acceptable excipient, or nutraceutically
acceptable excipient.
[0554] A composition described herein may further comprise an agent
(e.g., a pharmaceutical agent or diagnostic agent). In a
composition described herein, an agent may form an adduct (e.g.,
through covalent attachment and/or non-covalent interactions) with
a MON described herein (including a MON moiety of a BCPMON
described herein). In certain embodiments, a composition described
herein is useful in the delivery of the agent (e.g., an effective
amount of the agent) to a subject, tissue, or cell.
[0555] A composition described herein may further comprise a fluid
(e.g., a solvent, e.g., water, DMSO, acetonitrile, or a mixture
thereof)
[0556] Compositions of the disclosure may improve or increase the
delivery of an agent described herein to a subject, tissue, or
cell. In certain embodiments, the compositions increase the
delivery of the agent to a target tissue or target cell. In certain
embodiments, the target tissue is liver, spleen, or lung. In
certain embodiments, the target tissue is pancreas, kidney, uterus,
ovary, heart, thymus, fat, or muscle. In certain embodiments, the
target cell is a liver cell, spleen cell, lung cell, pancreas cell,
kidney cell, uterus cell, ovary cell, heart cell, thymus cell, or
muscle cell. In certain embodiments, the compositions selectively
deliver the agent to the target tissue or target cell (e.g., the
compositions deliver the agent to the target tissue in a greater
quantity in unit time than to a non-target tissue or deliver the
agent to the target cell in a greater quantity in unit time than to
a non-target cell).
[0557] The delivery of an agent described herein may be
characterized in various ways, such as the exposure, concentration,
and bioavailability of the agent. The exposure of an agent in a
subject, tissue, or cell may be defined as the area under the curve
(AUC) of the concentration of the agent in the subject, tissue, or
cell after administering or dosing the agent. In general, an
increase in exposure may be calculated by first taking the
difference in: (1) a first AUC, which is the AUC measured in a
subject, tissue, or cell administered or dosed with a composition
described herein; and (2) a second AUC, which is the AUC measured
in a subject, tissue, or cell administered or dosed with a control
composition; and then by dividing the difference by the second AUC.
Exposure of an agent may be measured in an appropriate animal
model. The concentration of an agent and, when appropriate, its
metabolite(s), in a subject, tissue, or cell is measured as a
function of time after administering or dosing the agent.
[0558] Concentration of an agent, and, when appropriate, of its
metabolite(s), in a subject, tissue, or cell, may be measured as a
function of time in vivo using an appropriate animal model. In
certain embodiments, the concentration of the agent is the
concentration of the agent in a target tissue or target cell. One
exemplary method of determining the concentration of an agent
involves dissecting of a tissue. The concentration of the agent may
be determined by HPLC or LC/MS analysis.
[0559] In some embodiments, a composition of the disclosure
increases the delivery of an agent described herein to a subject,
tissue, or cell due to the presence of a MON described herein. In
some embodiments, a composition of the disclosure increases the
delivery of an agent described herein to a subject, tissue, or cell
due to the presence of a BCPMON described herein. In some
embodiments, the composition increases the delivery of the agent
due to the presence of an adduct formed between the MON (including
a MON moiety of a BCPMON) and the agent. In some embodiments, the
presence of a MON or BCPMON described herein increase the delivery
of the agent by at least 10%, at least 20%, at least 30%, at least
40%, at least 50%, at least 100%, at least 2-fold, at least 3-fold,
at least 10-fold, at least 30-fold, at least 100-fold, at least
300-fold, or at least 1000-fold. In certain embodiments, a MON or
BCPMON described herein is present in the composition in an amount
sufficient to increase the delivery of the agent by an amount
described herein when administered in the composition compared to
the delivery of the agent when administered in the absence of the
MON or BCPMON.
[0560] Compositions described herein may deliver an agent
selectively to a tissue or cell. In certain embodiments, the tissue
or cell to which the agent is selectively delivered is a target
tissue or target cell, respectively. In certain embodiments, the
compositions deliver at least 10%, at least 20%, at least 30%, at
least 40%, at least 50%, at least 70%, at least 100%, at least
3-fold, at least 10-fold, at least 30-fold, at least 100-fold, at
least 300-fold, or at least 1000-fold more amount of the agent in
unit time to a target tissue than to a non-target tissue or to a
target cell than to a non-target cell. The amount of agent may be
measured by the exposure, concentration, and/or bioavailability of
the agent in a tissue or cell as described herein.
[0561] The compositions described herein (e.g., pharmaceutical
compositions) including one or more agents (e.g., pharmaceutical
agents) may be useful in treating and/or preventing a disease. In
certain embodiments, the compositions are useful in gene therapy.
In certain embodiments, the compositions are useful for treating
and/or preventing a genetic disease. In certain embodiments, the
compositions are useful for treating and/or preventing a
proliferative disease. In certain embodiments, the compositions are
useful for treating and/or preventing cancer. In certain
embodiments, the compositions are useful for treating and/or
preventing a benign neoplasm. In certain embodiments, the
compositions are useful for treating and/or preventing pathological
angiogenesis. In certain embodiments, the compositions are useful
for treating and/or preventing an inflammatory disease. In certain
embodiments, the compositions are useful for treating and/or
preventing an autoimmune disease. In certain embodiments, the
compositions are useful for treating and/or preventing a
hematological disease. In certain embodiments, the compositions are
useful for treating and/or preventing a neurological disease. In
certain embodiments, the compositions are useful for treating
and/or preventing a gastrointestinal disease. In certain
embodiments, the compositions are useful for treating and/or
preventing a liver disease. In certain embodiments, the
compositions are useful for treating and/or preventing a spleen
disease. In certain embodiments, the compositions are useful for
treating and/or preventing a respiratory disease. In certain
embodiments, the compositions are useful for treating and/or
preventing a lung disease. In certain embodiments, the compositions
are useful for treating and/or preventing hepatic carcinoma,
hypercholesterolemia, refractory anemia, or familial amyloid
neuropathy. In certain embodiments, the compositions are useful for
treating and/or preventing a painful condition. In certain
embodiments, the compositions are useful for treating and/or
preventing a genitourinary disease. In certain embodiments, the
compositions are useful for treating and/or preventing a
musculoskeletal condition. In certain embodiments, the compositions
are useful for treating and/or preventing an infectious disease. In
certain embodiments, the compositions are useful for treating
and/or preventing a psychiatric disorder. In certain embodiments,
the compositions are useful for treating and/or preventing a
metabolic disorder.
[0562] The agents may be provided in an effective amount in a
composition described herein. In certain embodiments, the effective
amount is a therapeutically effective amount. In certain
embodiments, the effective amount is a prophylactically effective
amount. In certain embodiments, the effective amount is an amount
effective for treating a disease described herein. In certain
embodiments, the effective amount is an amount effective for
preventing a disease described herein.
[0563] An effective amount of an agent may vary from about 0.001
mg/kg to about 1000 mg/kg in one or more dose administrations for
one or several days (depending on the mode of administration). In
certain embodiments, the effective amount per dose varies from
about 0.001 to about 1000 mg/kg, from about 0.01 to about 750
mg/kg, from about 0.1 to about 500 mg/kg, from about 1.0 to about
250 mg/kg, and from about 10.0 to about 150 mg/kg.
[0564] In certain embodiments, a composition described herein is in
the form of gels. In certain embodiments, the gels result from
self-assembly of the components of the composition. The agent to be
delivered by the gel may be in the form of a gas, liquid, or solid.
The MONs and/or BCPMONs described herein may be combined with
polymers (synthetic or natural), surfactants, cholesterol,
carbohydrates, proteins, lipids, lipidoids, etc. to form gels. The
gels may be further combined with an excipient to form the
composition. The gels are described in more detail herein.
[0565] The compositions described herein (e.g., pharmaceutical
compositions) can be prepared by any method known in the art (e.g.,
pharmacology). In certain embodiments, such preparatory methods
include the steps of bringing a MON or BCPMON described herein into
association with an agent described herein (i.e., the "active
ingredient"), optionally with a carrier or excipient, and/or one or
more other accessory ingredients, and then, if necessary and/or
desirable, shaping, and/or packaging the product into a desired
single- or multi-dose unit.
[0566] Compositions can be prepared, packaged, and/or sold in bulk,
as a single unit dose, and/or as a plurality of single unit doses.
A unit dose is a discrete amount of the composition comprising a
predetermined amount of the active ingredient. The amount of the
active ingredient is generally equal to the dosage of the active
ingredient which would be administered to a subject and/or a
convenient fraction of such a dosage such as, for example, one-half
or one-third of such a dosage.
[0567] Relative amounts of the active ingredient, the excipient
(e.g., the pharmaceutically or cosmetically acceptable excipient),
and/or any additional ingredients in a composition described herein
will vary, depending upon the identity, size, and/or condition of
the subject to whom the composition is administered and further
depending upon the route by which the composition is to be
administered. The composition may comprise between 0.1% and 100%
(w/w) active ingredient.
[0568] Excipients used in the manufacture of provided compositions
include inert diluents, dispersing and/or granulating agents,
surface active agents and/or emulsifiers, disintegrating agents,
binding agents, preservatives, buffering agents, lubricating
agents, and/or oils. Excipients such as cocoa butter and
suppository waxes, coloring agents, coating agents, sweetening,
flavoring, and perfuming agents may also be present in the
composition.
[0569] Exemplary diluents include calcium carbonate, sodium
carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate,
calcium hydrogen phosphate, sodium phosphate lactose, sucrose,
cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol,
inositol, sodium chloride, dry starch, cornstarch, powdered sugar,
and mixtures thereof.
[0570] Exemplary granulating and/or dispersing agents include
potato starch, corn starch, tapioca starch, sodium starch
glycolate, clays, alginic acid, guar gum, citrus pulp, agar,
bentonite, cellulose, and wood products, natural sponge,
cation-exchange resins, calcium carbonate, silicates, sodium
carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone),
sodium carboxymethyl starch (sodium starch glycolate),
carboxymethyl cellulose, cross-linked sodium carboxymethyl
cellulose (croscarmellose), methylcellulose, pregelatinized starch
(starch 1500), microcrystalline starch, water insoluble starch,
calcium carboxymethyl cellulose, magnesium aluminum silicate
(Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and
mixtures thereof.
[0571] Exemplary surface active agents and/or emulsifiers include
natural emulsifiers (e.g., acacia, agar, alginic acid, sodium
alginate, tragacanth, chondrux, cholesterol, xanthan, pectin,
gelatin, egg yolk, casein, wool fat, cholesterol, wax, and
lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and
Veegum (magnesium aluminum silicate)), long chain amino acid
derivatives, high molecular weight alcohols (e.g., stearyl alcohol,
cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene
glycol distearate, glyceryl monostearate, and propylene glycol
monostearate, polyvinyl alcohol), carbomers (e.g., carboxy
polymethylene, polyacrylic acid, acrylic acid polymer, and
carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g.,
carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl
cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene
sorbitan monolaurate (Tween.RTM. 20), polyoxyethylene sorbitan
(Tween.RTM. 60), polyoxyethylene sorbitan monooleate (Tween.RTM.
80), sorbitan monopalmitate (Span.RTM. 40), sorbitan monostearate
(Span.RTM. 60), sorbitan tristearate (Span.RTM. 65), glyceryl
monooleate, sorbitan monooleate (Span.RTM. 80), polyoxyethylene
esters (e.g., polyoxyethylene monostearate (Myrj.RTM. 45),
polyoxyethylene hydrogenated castor oil, polyethoxylated castor
oil, polyoxymethylene stearate, and Solutol.RTM.), sucrose fatty
acid esters, polyethylene glycol fatty acid esters (e.g.,
Cremophor.RTM.), polyoxyethylene ethers, (e.g., polyoxyethylene
lauryl ether (Brij.RTM. 30)), poly(vinyl-pyrrolidone), diethylene
glycol monolaurate, triethanolamine oleate, sodium oleate,
potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium
lauryl sulfate, Pluronic.RTM. F-68, Poloxamer P-188, cetrimonium
bromide, cetylpyridinium chloride, benzalkonium chloride, docusate
sodium, and mixtures thereof.
[0572] Exemplary binding agents include starch (e.g., cornstarch
and starch paste), gelatin, sugars (e.g., sucrose, glucose,
dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.),
natural and synthetic gums (e.g., acacia, sodium alginate, extract
of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks,
carboxymethylcellulose, methylcellulose, ethylcellulose,
hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, microcrystalline cellulose, cellulose acetate,
poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum.RTM.),
and larch arabogalactan), alginates, polyethylene oxide,
polyethylene glycol, inorganic calcium salts, silicic acid,
polymethacrylates, waxes, water, alcohol, and mixtures thereof.
[0573] Exemplary preservatives include antioxidants, chelating
agents, antimicrobial preservatives, antifungal preservatives,
antiprotozoan preservatives, alcohol preservatives, acidic
preservatives, and other preservatives. In certain embodiments, the
preservative is an antioxidant. In other embodiments, the
preservative is a chelating agent.
[0574] Exemplary antioxidants include alpha tocopherol, ascorbic
acid, acorbyl palmitate, butylated hydroxyanisole, butylated
hydroxytoluene, monothioglycerol, potassium metabisulfite,
propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite,
sodium metabisulfite, sodium sulfite, and mixtures thereof.
[0575] Exemplary chelating agents include
ethylenediaminetetraacetic acid (EDTA) and salts and hydrates
thereof (e.g., sodium edetate, disodium edetate, trisodium edetate,
calcium disodium edetate, and dipotassium edetateke), citric acid
and salts and hydrates thereof (e.g., citric acid monohydrate),
fumaric acid and salts and hydrates thereof, malic acid and salts
and hydrates thereof, phosphoric acid and salts and hydrates
thereof, tartaric acid and salts and hydrates thereof, and mixtures
thereof.
[0576] Exemplary antimicrobial preservatives include benzalkonium
chloride, benzethonium chloride, benzyl alcohol, bronopol,
cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol,
chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin,
hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol,
phenylmercuric nitrate, propylene glycol, thimerosal, and mixtures
thereof.
[0577] Exemplary antifungal preservatives include butyl paraben,
methyl paraben, ethyl paraben, propyl paraben, benzoic acid,
hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium
benzoate, sodium propionate, sorbic acid, and mixtures thereof.
[0578] Exemplary alcohol preservatives include ethanol,
polyethylene glycol, phenol, phenolic compounds, bisphenol,
chlorobutanol, hydroxybenzoate, phenylethyl alcohol, and mixtures
thereof.
[0579] Exemplary acidic preservatives include vitamin A, vitamin C,
vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic
acid, ascorbic acid, sorbic acid, phytic acid, and mixtures
thereof.
[0580] Other preservatives include tocopherol, tocopherol acetate,
deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA),
butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl
sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium
bisulfite, sodium metabisulfite, potassium sulfite, potassium
metabisulfite, Glydant.RTM. Plus, Phenonip.RTM., methylparaben,
Germall.RTM. 115, Germaben.RTM. II, Neolone.RTM., Kathon.RTM.,
Euxyl.RTM., and mixtures thereof.
[0581] Exemplary buffering agents include citrate buffer solutions,
acetate buffer solutions, phosphate buffer solutions, ammonium
chloride, calcium carbonate, calcium chloride, calcium citrate,
calcium glubionate, calcium gluceptate, calcium gluconate,
D-gluconic acid, calcium glycerophosphate, calcium lactate,
propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium
phosphate, phosphoric acid, tribasic calcium phosphate, calcium
hydroxide phosphate, potassium acetate, potassium chloride,
potassium gluconate, potassium mixtures, dibasic potassium
phosphate, monobasic potassium phosphate, potassium phosphate
mixtures, sodium acetate, sodium bicarbonate, sodium chloride,
sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic
sodium phosphate, sodium phosphate mixtures, tromethamine,
magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free
water, isotonic saline, Ringer's solution, ethyl alcohol, and
mixtures thereof.
[0582] Exemplary lubricating agents include magnesium stearate,
calcium stearate, stearic acid, silica, talc, malt, glyceryl
behanate, hydrogenated vegetable oils, polyethylene glycol, sodium
benzoate, sodium acetate, sodium chloride, leucine, magnesium
lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.
[0583] Exemplary natural oils include almond, apricot kernel,
avocado, babassu, bergamot, black current seed, borage, cade,
camomile, canola, caraway, carnauba, castor, cinnamon, cocoa
butter, coconut, cod liver, coffee, corn, cotton seed, emu,
eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd,
grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui
nut, lavandin, lavender, lemon, litsea cubeba, macademia nut,
mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange,
orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed,
pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood,
sasquana, savoury, sea buckthorn, sesame, shea butter, silicone,
soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut,
and wheat germ oils. Exemplary synthetic oils include, but are not
limited to, butyl stearate, caprylic triglyceride, capric
triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360,
isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol,
silicone oil, and mixtures thereof.
[0584] Additionally, the composition may further comprise an
apolipoprotein. Previous studies have reported that Apolipoprotein
E (ApoE) was able to enhance cell uptake and gene silencing for a
certain type of materials. See, e.g., Akinc, A., et al., Targeted
delivery of RNAi therapeutics with endogenous and exogenous
ligand-based mechanisms. Mol Ther. 18(7): p. 1357-64. In certain
embodiments, the apolipoprotein is ApoA, ApoB, ApoC, ApoE, or ApoH,
or an isoform thereof.
[0585] Liquid dosage forms for oral and parenteral administration
include emulsions, microemulsions, solutions, suspensions, syrups
and elixirs. In certain embodiments, the emulsions, microemulsions,
solutions, suspensions, syrups and elixirs are or cosmetically
acceptable emulsions, microemulsions, solutions, suspensions,
syrups and elixirs. In addition to the active ingredients, the
liquid dosage forms may comprise inert diluents commonly used in
the art such as, for example, water or other solvents, solubilizing
agents and emulsifiers such as ethyl alcohol, isopropyl alcohol,
ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, dimethylformamide, oils
(e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame
oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols
and fatty acid esters of sorbitan, and mixtures thereof. Besides
inert diluents, the oral compositions can include adjuvants such as
wetting agents, emulsifying and suspending agents, sweetening,
flavoring, and perfuming agents. In certain embodiments for
parenteral administration, the conjugates described herein are
mixed with solubilizing agents such as Cremophor.RTM., alcohols,
oils, modified oils, glycols, polysorbates, cyclodextrins,
polymers, and mixtures thereof.
[0586] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions can be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation can be a
sterile injectable solution, suspension, or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that can be employed are water, Ringer's solution, U.S.P.,
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or di-glycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0587] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0588] In order to prolong the effect of a drug, it is often
desirable to slow the absorption of the drug from subcutaneous or
intramuscular injection. This can be accomplished by the use of a
liquid suspension of crystalline or amorphous material with poor
water solubility. The rate of absorption of the drug then depends
upon its rate of dissolution, which, in turn, may depend upon
crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally administered drug form may be
accomplished by dissolving or suspending the drug in an oil
vehicle.
[0589] Compositions for rectal or vaginal administration are
typically suppositories which can be prepared by mixing the
conjugates with suitable non-irritating excipients or carriers such
as cocoa butter, polyethylene glycol, or a suppository wax which
are solid at ambient temperature but liquid at body temperature and
therefore melt in the rectum or vaginal cavity and release the
active ingredient.
[0590] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active ingredient is mixed with at least one inert, excipient
or carrier (e.g., pharmaceutically or cosmetically acceptable
excipient or carrier) such as sodium citrate or dicalcium phosphate
and/or (a) fillers or extenders such as starches, lactose, sucrose,
glucose, mannitol, and silicic acid, (b) binders such as, for
example, carboxymethylcellulose, alginates, gelatin,
polyvinylpyrrolidinone, sucrose, and acacia, (c) humectants such as
glycerol, (d) disintegrating agents such as agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, (e) solution retarding agents such
as paraffin, (f) absorption accelerators such as quaternary
ammonium compounds, (g) wetting agents such as, for example, cetyl
alcohol and glycerol monostearate, (h) absorbents such as kaolin
and bentonite clay, and (i) lubricants such as talc, calcium
stearate, magnesium stearate, solid polyethylene glycols, sodium
lauryl sulfate, and mixtures thereof. In the case of capsules,
tablets, and pills, the dosage form may include a buffering
agent.
[0591] Solid compositions of a similar type can be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like. The solid dosage forms of
tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings and other
coatings well known in the art of pharmacology. They may optionally
comprise opacifying agents and can be of a composition that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed
manner. Examples of encapsulating compositions which can be used
include polymeric substances and waxes. Solid compositions of a
similar type can be employed as fillers in soft and hard-filled
gelatin capsules using such excipients as lactose or milk sugar as
well as high molecular weight polyethylene glycols and the
like.
[0592] The active ingredient can be in a micro-encapsulated form
with one or more excipients as noted above. The solid dosage forms
of tablets, dragees, capsules, pills, and granules can be prepared
with coatings and shells such as enteric coatings, release
controlling coatings, and other coatings well known in the
formulation art. In such solid dosage forms the active ingredient
can be admixed with at least one inert diluent such as sucrose,
lactose, or starch. Such dosage forms may comprise, as is normal
practice, additional substances other than inert diluents, e.g.,
tableting lubricants and other tableting aids such a magnesium
stearate and microcrystalline cellulose. In the case of capsules,
tablets and pills, the dosage forms may comprise buffering agents.
They may optionally comprise opacifying agents and can be of a
composition that they release the active ingredient(s) only, or
preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner. Examples of encapsulating agents
which can be used include polymeric substances and waxes.
[0593] Dosage forms for topical and/or transdermal administration
of a composition of this disclosure may include ointments, pastes,
creams, lotions, gels, powders, solutions, sprays, inhalants,
and/or patches. Generally, the active ingredient is admixed under
sterile conditions with a carrier or excipient and/or any needed
preservatives and/or buffers as can be required. Additionally, the
present disclosure contemplates the use of transdermal patches,
which often have the added advantage of providing controlled
delivery of an active ingredient to the body. Such dosage forms can
be prepared, for example, by dissolving and/or dispensing the
active ingredient in the proper medium. Alternatively or
additionally, the rate can be controlled by either providing a rate
controlling membrane and/or by dispersing the active ingredient in
a polymer matrix and/or gel.
[0594] Suitable devices for use in delivering intradermal
compositions described herein include short needle devices.
Intradermal compositions can be administered by devices which limit
the effective penetration length of a needle into the skin.
Alternatively or additionally, conventional syringes can be used in
the classical mantoux method of intradermal administration. Jet
injection devices which deliver liquid vaccines to the dermis via a
liquid jet injector and/or via a needle which pierces the stratum
corneum and produces a jet which reaches the dermis are suitable.
Ballistic powder/particle delivery devices which use compressed gas
to accelerate the agent in powder form through the outer layers of
the skin to the dermis are suitable.
[0595] Formulations suitable for topical administration include,
but are not limited to, liquid and/or semi-liquid preparations such
as liniments, lotions, oil-in-water and/or water-in-oil emulsions
such as creams, ointments, and/or pastes, and/or solutions and/or
suspensions. Topically administrable formulations may, for example,
comprise from about 1% to about 10% (w/w) active ingredient,
although the concentration of the active ingredient can be as high
as the solubility limit of the active ingredient in the solvent.
Formulations for topical administration may further comprise one or
more of the additional ingredients described herein.
[0596] A composition described herein can be prepared, packaged,
and/or sold in a formulation suitable for pulmonary administration
via the buccal cavity. Such a formulation may comprise dry
particles which comprise the active ingredient. Dry powder
compositions may include a solid fine powder diluent such as sugar
and are conveniently provided in a unit dose form.
[0597] Low boiling propellants generally include liquid propellants
having a boiling point of below 65.degree. F. at atmospheric
pressure. Generally the propellant may constitute 50 to 99.9% (w/w)
of the composition, and the active ingredient may constitute 0.1 to
20% (w/w) of the composition. The propellant may further comprise
additional ingredients such as a liquid non-ionic and/or solid
anionic surfactant and/or a solid diluent (which may have a
particle size of the same order as particles comprising the active
ingredient).
[0598] Compositions described herein formulated for pulmonary
delivery may provide the active ingredient in the form of droplets
of a solution and/or suspension. Such formulations can be prepared,
packaged, and/or sold as aqueous and/or dilute alcoholic solutions
and/or suspensions, optionally sterile, comprising the active
ingredient, and may conveniently be administered using any
nebulization and/or atomization device. Such formulations may
further comprise one or more additional ingredients including, but
not limited to, a flavoring agent such as saccharin sodium, a
volatile oil, a buffering agent, a surface active agent, and/or a
preservative such as methylhydroxybenzoate. The droplets provided
by this route of administration may have an average diameter in the
range from about 0.1 to about 200 nanometers.
[0599] Formulations described herein as being useful for pulmonary
delivery are useful for intranasal delivery of a composition
described herein. Another formulation suitable for intranasal
administration is a coarse powder comprising the active ingredient
and having an average particle from about 0.2 to 500 micrometers.
Such a formulation is administered by rapid inhalation through the
nasal passage from a container of the powder held close to the
nares.
[0600] Formulations for nasal administration may, for example,
comprise from about as little as 0.1% (w/w) to as much as 100%
(w/w) of the active ingredient, and may comprise one or more of the
additional ingredients described herein. A composition described
herein can be prepared, packaged, and/or sold in a formulation for
buccal administration. Such formulations may, for example, be in
the form of tablets and/or lozenges made using conventional
methods, and may contain, for example, 0.1 to 20% (w/w) active
ingredient, the balance comprising an orally dissolvable and/or
degradable composition and, optionally, one or more of the
additional ingredients described herein. Alternately, formulations
for buccal administration may comprise a powder and/or an
aerosolized and/or atomized solution and/or suspension comprising
the active ingredient. Such powdered, aerosolized, and/or
aerosolized formulations, when dispersed, may have an average
particle and/or droplet size in the range from about 0.1 to about
200 nanometers, and may further comprise one or more of the
additional ingredients described herein.
[0601] A composition described herein can be prepared, packaged,
and/or sold in a formulation for ophthalmic administration. Such
formulations may, for example, be in the form of eye drops
including, for example, a 0.1/1.0% (w/w) solution and/or suspension
of the active ingredient in an aqueous or oily liquid carrier or
excipient. Such drops may further comprise buffering agents, salts,
and/or one or more other of the additional ingredients described
herein. Other opthalmically-administrable formulations which are
useful include those which comprise the active ingredient in
microcrystalline form and/or in a liposomal preparation. Ear drops
and/or eye drops are also contemplated as being within the scope of
this disclosure.
[0602] Although the descriptions of compositions provided herein
are principally directed to compositions which are suitable for
administration to humans, it will be understood by the skilled
artisan that such compositions are generally suitable for
administration to animals of all sorts. Modification of
compositions suitable for administration to humans in order to
render the compositions suitable for administration to various
animals is well understood, and the ordinarily skilled veterinary
pharmacologist can design and/or perform such modification with
ordinary experimentation.
[0603] Metal organic nanostructures and BCPMONs described herein
are typically formulated in dosage unit form for ease of
administration and uniformity of dosage. It will be understood,
however, that the total daily usage of the compositions of the
present disclosure will be decided by the attending physician
within the scope of sound medical judgment. The specific
therapeutically effective dose level for any particular subject or
organism will depend upon a variety of factors including the
disease being treated and the severity of the disorder, the
activity of the specific active ingredient employed, the specific
composition employed, the age, body weight, general health, sex,
and diet of the subject, the time of administration, route of
administration, and rate of excretion of the specific active
ingredient employed, the duration of the treatment, drugs used in
combination or coincidental with the specific active ingredient
employed, and like factors well known in the medical arts.
[0604] The compositions described herein can be administered by any
suitable route, including enteral (e.g., oral), parenteral,
intravenous, intramuscular, intra-arterial, intramedullary,
intrathecal, subcutaneous, intraventricular, transdermal,
interdermal, rectal, intravaginal, intraperitoneal, topical (as by
powders, ointments, creams, and/or drops), mucosal, nasal, bucal,
sublingual; by intratracheal instillation, bronchial instillation,
and/or inhalation; and/or as an oral spray, nasal spray, and/or
aerosol. In certain embodiments, the compositions are administered
by oral administration, intravenous administration (e.g., systemic
intravenous injection), regional administration via blood and/or
lymph supply, and/or direct administration to an affected site. In
general, the most appropriate route of administration will depend
upon a variety of factors including the nature of the agent (e.g.,
its stability in the environment of the gastrointestinal tract),
and/or the condition of the subject (e.g., whether the subject is
able to tolerate oral administration).
[0605] The exact amount of an agent required to achieve an
effective amount will vary from subject to subject, depending, for
example, on species, age, and general condition of a subject,
severity of the side effects or disorder, identity of the
particular agent, mode of administration, and the like. The desired
dosage can be delivered three times a day, two times a day, once a
day, every other day, every third day, every week, every two weeks,
every three weeks, or every four weeks. In certain embodiments, the
desired dosage can be delivered using multiple administrations
(e.g., two, three, four, five, six, seven, eight, nine, ten,
eleven, twelve, thirteen, fourteen, or more administrations).
[0606] In certain embodiments, an effective amount of an agent for
administration one or more times a day to a 70 kg adult human may
comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about
2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about
1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000
mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about
10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of an
agent per unit dosage form.
[0607] In certain embodiments, the agents described herein may be
at dosage levels sufficient to deliver from about 0.001 mg/kg to
about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg,
preferably from about 0.1 mg/kg to about 40 mg/kg, preferably from
about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about
10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and more
preferably from about 1 mg/kg to about 25 mg/kg, of subject body
weight per day, one or more times a day, to obtain the desired
therapeutic and/or prophylactic effect.
[0608] It will be appreciated that dose ranges as described herein
provide guidance for the administration of provided compositions to
an adult. The amount to be administered to, for example, a child or
an adolescent can be determined by a medical practitioner or person
skilled in the art and can be lower or the same as that
administered to an adult.
[0609] Compositions described herein may further include a
hydrophilic polymer (e.g., polyethylene glycol (PEG)). The
compositions described herein may further include a lipid (e.g., a
steroid, a substituted or unsubstituted cholesterol, or a
polyethylene glycol (PEG)-containing material). In certain
embodiments, the lipid included in the compositions is a
triglyceride, a driglyceride, a PEGylated lipid,
dimyristoyl-PEG2000 (DMG-PEG2000), a phospholipid (e.g.,
1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)),
dioleoylphosphatidylethanolamine (DOPE), a substituted or
unsubstituted cholesterol, a steroid an apolipoprotein, or a
combination thereof. In certain embodiments, the compositions
include two components selected from the group consisting of the
following components: a hydrophilic polymer, a triglyceride, a
driglyceride, a PEGylated lipid, a phospholipid, a steroid, a
substituted or unsubstituted cholesterol, and an apolipoprotein. In
certain embodiments, the compositions include three components
selected from the group consisting of the following components: a
hydrophilic polymer, a triglyceride, a driglyceride, a PEGylated
lipid, a phospholipid, a steroid, a substituted or unsubstituted
cholesterol, and an apolipoprotein. In certain embodiments, the
compositions include at least four components selected from the
group consisting of the following components: a hydrophilic
polymer, a triglyceride, a driglyceride, a PEGylated lipid, a
phospholipid, a steroid, a substituted or unsubstituted
cholesterol, and an apolipoprotein. In certain embodiments, the
compositions include a hydrophilic polymer, a phospholipid, a
steroid, and a substituted or unsubstituted cholesterol. In certain
embodiments, the compositions include PEG, DSPC, and substituted or
unsubstituted cholesterol. In certain embodiments, the additional
materials are approved by a regulatory agency, such as the U.S.
FDA, for human and/or veterinary use.
[0610] Compositions described herein may be useful in other
applications, e.g., non-medical applications. Nutraceutical
compositions described herein may be useful in the delivery of an
effective amount of a nutraceutical, e.g., a dietary supplement, to
a subject in need thereof. Cosmetic compositions described herein
may be formulated as a cream, ointment, balm, paste, film, or
liquid, etc., and may be useful in the application of make-up, hair
products, and materials useful for personal hygiene, etc.
Compositions described herein may be useful for other non-medical
applications, e.g., such as an emulsion, emulsifier, or coating,
useful, for example, as a food component, for extinguishing fires,
for disinfecting surfaces, for oil cleanup, and/or as a bulk
material.
Agents (Agents to be Delivered)
[0611] Agents that are delivered by the systems (e.g.,
pharmaceutical compositions) described herein may be pharmaceutical
(e.g., therapeutic or prophylactic), diagnostic, cosmetic, or
nutraceutical agents. Any chemical compound to be administered to a
subject or to be contacted with a tissue or cell may be delivered
using the MONs, BCPMONs, and/or compositions described herein. The
agent may be a small molecule (e.g., a small organic molecule or
small inorganic molecule), protein, peptide, polynucleotide,
targeting agent, isotopically labeled chemical compound, vaccine,
or immunological agent. The agent may be an agent useful in
bioprocessing (e.g., intracellular manufacturing of proteins, such
as a cell's bioprocessing of a commercially useful chemical or
fuel). For example, intracellular delivery of an agent may be
useful in bioprocessing by maintaining the cell's health and/or
growth, e.g., in the manufacturing of proteins. Any chemical
compound to be administered to a subject or contacted with a tissue
or cell may be delivered to the subject, tissue, or cell using the
compositions described herein.
[0612] Exemplary agents that may be included in a composition
described herein include, but are not limited to, small molecules,
organometallic compounds, polynucleotides, proteins, peptides,
carbohydrates, monosaccharides, oligosaccharides, polysaccharides,
nucleoproteins, mucoproteins, lipoproteins, small molecules linked
to proteins, glycoproteins, steroids, nucleotides,
oligonucleotides, polynucleotides, nucleosides, antisense
oligonucleotides, lipids, hormones, vitamins, cells, metals,
targeting agents, isotopically labeled chemical compounds, drugs
(e.g., compounds approved for human or veterinary use by the U.S.
Food and Drug Administration as provided in the Code of Federal
Regulations), vaccines, immunological agents, agents useful in
bioprocessing, and mixtures thereof. The targeting agents are
described in more detail herein. In certain embodiments, the agents
are nutraceutical agents. In certain embodiments, the agents are
pharmaceutical agents (e.g., a therapeutic or prophylactic agent).
In certain embodiments, the agent is an antibiotic agent (e.g., an
anti-bacterial, anti-viral, or anti-fungal agent), anesthetic,
steroidal agent, anti-proliferative agent, anti-inflammatory agent,
anti-angiogenesis agent, anti-neoplastic agent, anti-cancer agent,
anti-diabetic agent, antigen, vaccine, antibody, decongestant,
antihypertensive, sedative, birth control agent, progestational
agent, anti-cholinergic, analgesic, immunosuppressant,
anti-depressant, anti-psychotic, .beta.-adrenergic blocking agent,
diuretic, cardiovascular active agent, vasoactive agent,
non-steroidal, nutritional agent, anti-allergic agent, or
pain-relieving agent. Vaccines may comprise isolated proteins or
peptides, inactivated organisms and viruses, dead organisms and
viruses, genetically altered organisms or viruses, and cell
extracts. Therapeutic and prophylactic agents may be combined with
interleukins, interferon, cytokines, and adjuvants such as cholera
toxin, alum, and Freund's adjuvant, etc. In certain embodiments,
the agent is a small molecule. In certain embodiments, the agent is
an anti-cancer agent (e.g., an anti-cancer agent disclosed in U.S.
Patent Application Publication No. US 2003/065023). In certain
embodiments, the agent is doxorubicin.
[0613] In certain embodiments, an agent described herein is a
polynucleotide. In certain embodiments, the agent is plasmid DNA
(pDNA). In certain embodiments, the agent is single-stranded DNA
(ssDNA), double-stranded DNA (dsDNA), genomic DNA (gDNA),
complementary DNA (cDNA), antisense DNA, chloroplast DNA (ctDNA or
cpDNA), microsatellite DNA, mitochondrial DNA (mtDNA or mDNA),
kinetoplast DNA (kDNA), provirus, lysogen, repetitive DNA,
satellite DNA, or viral DNA. In certain embodiments, the agent is
RNA. In certain embodiments, the agent is small interfering RNA
(siRNA). In certain embodiments, the agent is messenger RNA (mRNA).
In certain embodiments, the agent is single-stranded RNA (ssRNA),
double-stranded RNA (dsRNA), small interfering RNA (siRNA),
precursor messenger RNA (pre-mRNA), small hairpin RNA or short
hairpin RNA (shRNA), microRNA (miRNA), guide RNA (gRNA), transfer
RNA (tRNA), antisense RNA (asRNA), heterogeneous nuclear RNA
(hnRNA), coding RNA, non-coding RNA (ncRNA), long non-coding RNA
(long ncRNA or lncRNA), satellite RNA, viral satellite RNA, signal
recognition particle RNA, small cytoplasmic RNA, small nuclear RNA
(snRNA), ribosomal RNA (rRNA), Piwi-interacting RNA (piRNA),
polyinosinic acid, ribozyme, flexizyme, small nucleolar RNA
(snoRNA), spliced leader RNA, viral RNA, or viral satellite RNA. In
certain embodiments, the agent is an RNA that carries out RNA
interference (RNAi). The phenomenon of RNAi is discussed in greater
detail, for example, in the following references: Elbashir et al.,
2001, Genes Dev., 15:188; Fire et al., 1998, Nature, 391:806;
Tabara et al., 1999, Cell, 99:123; Hammond et al., Nature, 2000,
404:293; Zamore et al., 2000, Cell, 101:25; Chakraborty, 2007,
Curr. Drug Targets, 8:469; and Morris and Rossi, 2006, Gene Ther.,
13:553. In certain embodiments, upon delivery of an RNA into a
subject, tissue, or cell, the RNA is able to interfere with the
expression of a specific gene in the subject, tissue, or cell. In
certain embodiments, the agent is a pDNA, siRNA, mRNA, or a
combination thereof.
[0614] In certain embodiments, the polynucleotide may be provided
as an antisense agent or RNAi. See, e.g., Fire et al., Nature
391:806-811, 1998. Antisense therapy is meant to include, e.g.,
administration or in situ provision of single- or double-stranded
polynucleotides, or derivatives thereof, which specifically
hybridize, e.g., bind, under cellular conditions, with cellular
mRNA and/or genomic DNA, or mutants thereof, so as to inhibit the
expression of the encoded protein, e.g., by inhibiting
transcription and/or translation. See, e.g., Crooke, "Molecular
mechanisms of action of antisense drugs," Biochim. Biophys. Acta
1489(1):31-44, 1999; Crooke, "Evaluating the mechanism of action of
anti-proliferative antisense drugs," Antisense Nucleic Acid Drug
Dev. 10(2):123-126, discussion 127, 2000; Methods in Enzymology
volumes 313-314, 1999. The binding may be by conventional base pair
complementarity, or, for example, in the case of binding to DNA
duplexes, through specific interactions in the major groove of the
double helix (i.e., triple helix formation). See, e.g., Chan et
al., J. Mol. Med. 75(4):267-282, 1997.
[0615] The RNA and/or RNAi described herein can be designed and/or
predicted using one or more of a large number of available
algorithms. To give but a few examples, the following resources can
be utilized to design and/or predict polynucleotides: algorithms
found at Alnylum Online; Dharmacon Online; OligoEngine Online;
Molecula Online; Ambion Online; BioPredsi Online; RNAi Web Online;
Chang Bioscience Online; Invitrogen Online; LentiWeb Online
GenScript Online; Protocol Online; Reynolds et al., 2004, Nat.
Biotechnol., 22:326; Naito et al., 2006, Nucleic Acids Res.,
34:W448; Li et al., 2007, RNA, 13:1765; Yiu et al., 2005,
Bioinformatics, 21:144; and Jia et al., 2006, BMC Bioinformatics,
7: 271.
[0616] The polynucleotide included in a composition described
herein may be of any size or sequence, and they may be single- or
double-stranded. In certain embodiments, the polynucleotide
includes at least 30, at least 100, at least 300, at least 1,000,
at least 3,000, or at least 10,000 base pairs. In certain
embodiments, the polynucleotide includes not more than 10,000, not
more than 3,000, not more than 1,000, not more than 300, not more
than 100, or not more than 30 base pairs. Combinations of the above
ranges (e.g., at least 100 and not more than 1,000) are also within
the scope of the disclosure. The polynucleotide may be provided by
any suitable means known in the art. In certain embodiments, the
polynucleotide is engineered using recombinant techniques. See,
e.g., Ausubel et al., Current Protocols in Molecular Biology (John
Wiley & Sons, Inc., New York, 1999); Molecular Cloning: A
Laboratory Manual, 2nd Ed., ed. by Sambrook, Fritsch, and Maniatis
(Cold Spring Harbor Laboratory Press: 1989). The polynucleotide may
also be obtained from natural sources and purified from
contaminating components found normally in nature. The
polynucleotide may also be chemically synthesized in a laboratory.
In certain embodiments, the polynucleotide is synthesized using
standard solid phase chemistry. The polynucleotide may be isolated
and/or purified. In certain embodiments, the polynucleotide is
substantially free of impurities. In certain embodiments, the
polynucleotide is at least 50%, at least 60%, at least 70%, at
least 80%, at least 90%, at least 95%, or at least 99% free of
impurities.
[0617] The polynucleotide may be modified by physical, chemical,
and/or biological means. The modifications include methylation,
phosphorylation, and/or end-capping, etc. In certain embodiments,
the modifications lead to increased stability of the
polynucleotide.
[0618] Wherever a polynucleotide is employed in the present
disclosure, a derivative of the polynucleotide may also be used.
These derivatives include products resulted from modifications of
the polynucleotide in the base moieties, sugar moieties, and/or
phosphate moieties of the polynucleotide. Modified base moieties
include, but are not limited to, 2-aminoadenosine, 2-thiothymidine,
inosine, pyrrolo-pyrimidine, 3-methyl adenosine, 5-methylcytidine,
C5-bromouridine, C5-fluorouridine, C5-iodouridine,
C5-propynyl-uridine, C5-propynyl-cytidine, C5-methylcytidine,
7-deazaadenosine, 7-deazaguanosine, 8-oxoadenosine, 8-oxoguanosine,
O(6)-methylguanine, and 2-thiocytidine. Modified sugar moieties
include, but are not limited to, 2'-fluororibose, ribose,
2'-deoxyribose, 3'-azido-2',3'-dideoxyribose, 2',3'-dideoxyribose,
arabinose (the 2'-epimer of ribose), acyclic sugars, and hexoses.
The nucleosides may be strung together by linkages other than the
phosphodiester linkage found in naturally occurring DNA and RNA.
Modified linkages include, but are not limited to, phosphorothioate
and 5'-N-phosphoramidite linkages. Combinations of the various
modifications may be used in a single polynucleotide. These
modified polynucleotides may be provided by any suitable means
known in the art; however, as will be appreciated by those of skill
in the art, the modified polynucleotides may be prepared using
synthetic chemistry in vitro.
[0619] The polynucleotide described herein may be in any form, such
as a circular plasmid, a linearized plasmid, a cosmid, a viral
genome, a modified viral genome, or an artificial chromosome.
[0620] The polynucleotide described herein may be of any sequence.
In certain embodiments, the polynucleotide encodes a protein or
peptide. The encoded protein may be an enzyme, structural protein,
receptor, soluble receptor, ion channel, active (e.g.,
pharmaceutically active) protein, cytokine, interleukin, antibody,
antibody fragment, antigen, coagulation factor, albumin, growth
factor, hormone, or insulin, etc. The polynucleotide may also
comprise regulatory regions to control the expression of a gene.
These regulatory regions may include, but are not limited to,
promoters, enhancer elements, repressor elements, TATA boxes,
ribosomal binding sites, and stop sites for transcription. In
certain embodiments, the polynucleotide is not intended to encode a
protein. For example, the polynucleotide may be used to fix an
error in the genome of the cell being transfected.
[0621] In certain embodiments, the polynucleotide described herein
comprises a sequence encoding an antigenic peptide or protein. A
composition containing the polynucleotide can be delivered to a
subject to induce an immunologic response sufficient to decrease
the chance of a subsequent infection and/or lessen the symptoms
associated with such an infection. The polynucleotide of these
vaccines may be combined with interleukins, interferon, cytokines,
and/or adjuvants described herein.
[0622] The antigenic protein or peptides encoded by the
polynucleotide may be derived from bacterial organisms, such as
Streptococccus pneumoniae, Haemophilus influenzae, Staphylococcus
aureus, Streptococcus pyrogenes, Corynebacterium diphtheriae,
Listeria monocytogenes, Bacillus anthracis, Clostridium tetani,
Clostridium botulinum, Clostridium perfringens, Neisseria
meningitidis, Neisseria gonorrhoeae, Streptococcus mutans,
Pseudomonas aeruginosa, Salmonella typhi, Haemophilus
parainfluenzae, Bordetella pertussis, Francisella tularensis,
Yersinia pestis, Vibrio cholerae, Legionella pneumophila,
Mycobacterium tuberculosis, Mycobacterium leprae, Treponema
pallidum, Leptospirosis interrogans, Borrelia burgdorferi, and
Camphylobacter jejuni; from viruses, such as smallpox virus,
influenza A virus, influenza B virus, respiratory syncytial virus,
parainfluenza virus, measles virus, HIV virus, varicella-zoster
virus, herpes simplex 1 virus, herpes simplex 2 virus,
cytomegalovirus, Epstein-Barr virus, rotavirus, rhinovirus,
adenovirus, papillomavirus, poliovirus, mumps virus, rabies virus,
rubella virus, coxsackieviruses, equine encephalitis virus,
Japanese encephalitis virus, yellow fever virus, Rift Valley fever
virus, hepatitis A virus, hepatitis B virus, hepatitis C virus,
hepatitis D virus, and hepatitis E virus; and from fungal,
protozoan, or parasitic organisms, such as Cryptococcus neoformans,
Histoplasma capsulatum, Candida albicans, Candida tropicalis,
Nocardia asteroides, Rickettsia ricketsii, Rickettsia typhi,
Mycoplasma pneumoniae, Chlamydial psittaci, Chlamydial trachomatis,
Plasmodium falciparum, Trypanosoma brucei, Entamoeba histolytica,
Toxoplasma gondii, Trichomonas vaginalis, and Schistosoma
mansoni.
[0623] An agent described herein may be covalently or
non-covalently attached to (e.g., complexed to and/or encapsulated
in) a MON or BCPMON (e.g., attached to a MON of the BCPMON)
described herein, or included in a composition described herein. In
certain embodiments, at least one instance of the MON encapsulates
the agent. In certain embodiments, at least one molecule of the
agent is not encapsulated in any instance of the MON. In certain
embodiments, upon delivery of the agent into a cell, the agent is
able to interfere with the expression of a specific gene in the
cell.
[0624] In certain embodiments, an agent described herein may be a
mixture of two or more agents that may be useful as, e.g.,
combination therapies. A composition including the mixture can be
used to achieve a synergistic effect. In certain embodiments, the
composition including the mixture can be used to improve the
activity and/or bioavailability, reduce and/or modify the
metabolism, inhibit the excretion, and/or modify the distribution
of at least one of the two or more agents in a subject, tissue, or
cell to which the mixture is administered or dosed. It will also be
appreciated that the composition including the mixture may achieve
a desired effect for the same disorder, and/or it may achieve
different effects. The two or more agents in the mixture may be
useful for treating and/or preventing a same disease or different
diseases described herein.
[0625] The compositions (e.g., pharmaceutical compositions)
described herein can be administered concurrently with, prior to,
or subsequent to the one or more agents (e.g., pharmaceutical
agents). Each one of the agents may be administered at a dose
and/or on a time schedule determined for that agent. The agents may
also be administered together with each other and/or with the
composition described herein in a single dose or administered
separately in different doses. The particular combination to employ
in a regimen will take into account compatibility of the agents
and/or the desired therapeutic and/or prophylactic effect to be
achieved. In general, it is expected that the agents utilized in
combination be utilized at levels that do not exceed the levels at
which they are utilized individually. In some embodiments, the
levels utilized in combination will be lower than those utilized
individually.
Targeting Agents
[0626] Since it is often desirable to target a particular cell,
collection of cells, or tissue, a composition described herein may
further include targeting moieties or targeting agents. In certain
embodiments, a MON described herein (including a MON moiety of a
BCPMON described herein) is modified to include targeting moieties
or targeting agents. For example, a targeting moiety or targeting
agent may be included throughout a MON or BCPMON (e.g., throughout
a MON of the BCPMON) described herein or may be only at the surface
(e.g., outer or inner surface) of the MON or BCPMON (e.g., at the
surface of a MON of the BCPMON). A targeting agent may be a
protein, peptide, carbohydrate, glycoprotein, lipid, small
molecule, or polynucleotide, and a targeting moiety may be a
fragment of the targeting agent. The targeting moiety or targeting
agent may be used to target specific cells or tissues or may be
used to promote endocytosis or phagocytosis of the MON and/or
BCPMON. The targeting moieties or targeting agents include the ones
known in the art. See, e.g., Cotten et al., Methods Enzym. 217:618,
1993. Examples of the targeting moieties and targeting agents
include, but are not limited to, antibodies, proteins, peptides,
carbohydrates, small molecules, metals, receptor ligands, sialic
acid, aptamers, and fragments thereof. If a targeting moiety or
targeting agent is included throughout a MON or BCPMON, the
targeting agent may be included in the mixture that is used to form
the MON or BCPMON. If the targeting agent is only on the surface of
a MON or BCPMON, the targeting agent may be associated with (e.g.,
by covalent or non-covalent (e.g., electrostatic, hydrophobic,
hydrogen bonding, van der Waals, .pi.-.pi. stacking) interactions)
the MON or BCPMON using standard chemical techniques.
Adducts of a MON and an Agent
[0627] The present disclosure contemplates that the MONs described
herein (including the MON moieties of the BCPMONs described herein)
are useful in the delivery of an agent described herein (e.g., a
small molecule, peptide, protein, or a polynucleotide) to a
subject, tissue, or cell. Without wishing to be bound by any
particular theory, the MONs have several desirable properties that
make a composition that includes the MONs and an agent suitable for
delivering the agent to a subject, tissue, or cell. Encapsulation
of an agent within a MON described herein may have desirable
properties for delivering an agent to a subject, tissue, or cell,
including protection from degradation of the agent by ubiquitous
nucleases, passive and active targeting, and/or evasion of
endosomal Toll-like receptors. Other desirable properties include:
1) the ability of the MONs to form an adduct with and "protect" the
agent that may otherwise be labile (e.g., labile at least due to
chemical and/or enzymatical (e.g., by nucleases) degradation); 2)
the ability of the MONs to buffer the pH in an endosome of the
cell; 3) the ability of the MONs to act as a "proton sponge" and
cause endosomolysis; and 4) the ability of the MONs to
substantially neutralize the negative or positive charges of the
agent. Challenges to the efficient delivery of an agent exist,
including particle dissociation via serum proteins, cellular
uptake, endosomal escape, and appropriate intracellular
disassembly. To address some of these challenges, single parameter
studies that evaluate the effect of chemical structure on a single
biological property or on delivery performance have been reported.
Furthermore, high-throughput synthetic methods have been exploited
for the accelerated discovery of potent lipid nanoparticles (LNPs)
and evaluation of structure activity relationships (SARs). In spite
of these efforts, the relationships between physicochemical
properties of nanoparticles and biological barriers, and that
between biological barriers and gene silencing activity remain
unclear. This lack of clarity has also resulted in poor in vitro-in
vivo translation.
[0628] In certain embodiments, a MON described herein encapsulates
an agent described herein. In certain embodiments, the ratio of the
amount of a MON described herein to the amount of an agent
encapsulated in the MON is at least 1:1, at least 2:1, at least
5:1, at least 10:1, at least 20:1, at least 50:1, at least 100:1,
at least 200:1, or at least 500:1 mol/mol. In certain embodiments,
the ratio of the MON or BCPMON to the agent is not more than 500:1,
not more than 200:1, not more than 100:1, not more than 50:1, not
more than 20:1, not more than 10:1, not more than 5:1, not more
than 2:1, or not more than 1:1 mol/mol. Combinations of the above
ranges (e.g., at least 1:1 and not more than 100:1) are also within
the scope of the disclosure.
[0629] A MON and agent described herein may form an adduct. An
adduct may be formed by covalently attaching an agent to a MON or
by non-covalent interactions (e.g., electrostatic interactions,
hydrophobic interactions, hydrogen bonding, van der Waals
interactions, and/or n-stacking) between an agent and a MON. An
agent may be contacted with a MON, or the components thereof (e.g.,
ligands of Formula (A), (C), or (B) and transition metal ions, and
optionally anionic counterions), under conditions suitable to form
an adduct.
Micelles, Liposomes, and Lipoplexes
[0630] A composition including a MON and agent described herein may
be in the form of a micelle or liposome. In certain embodiments,
the MONs are in the form of a micelle or liposome. An agent
described herein may be inside a micelle or liposome, and a MON
described herein may be inside the micelle or liposome. In certain
embodiments, in a micelle or liposome, an agent is encapsulated in
a MON. Micelles and liposomes are typically useful in delivering an
agent, such as a hydrophobic agent, to a subject, tissue, or cell.
When the micelle or liposome is complexed with (e.g., encapsulates
or covers) a polynucleotide, the resulting complex may be referred
to as a "lipoplex." Many techniques for preparing micelles and
liposomes are known in the art, and any such method may be used to
make micelles and liposomes.
[0631] In certain embodiments, liposomes are formed through
spontaneous assembly. In some embodiments, liposomes are formed
when thin lipid films or lipid cakes are hydrated and stacks of
lipid crystalline bilayers become fluid and swell. The hydrated
lipid sheets detach during agitation and self-close to form large,
multilamellar vesicles (LMV). This may prevent interaction of water
with the hydrocarbon core of the bilayers at the edges. Once these
liposomes have formed, reducing the size of the liposomes can be
modified through input of sonic energy (sonication) or mechanical
energy (extrusion). See, e.g., Walde, P. "Preparation of Vesicles
(Liposomes)" In Encylopedia of Nanoscience and Nanotechnology;
Nalwa, H. S. Ed. American Scientific Publishers: Los Angeles, 2004;
Vol. 9, pp. 43-79; Szoka et al., "Comparative Properties and
Methods of Preparation of Lipid Vesicles (Liposomes)" Ann. Rev.
Biophys. Bioeng. 9:467-508, 1980; each of which is incorporated
herein by reference. The preparation of lipsomes may involve
preparing a MON described herein for hydration, hydrating the MONs
with agitation, and sizing the vesicles to achieve a homogenous
distribution of liposomes. A MON described herein may be first
dissolved in a solvent in a container to result in a homogeneous
mixture. The solvent is then removed to form a film. This film is
thoroughly dried to remove residual amount of the solvent, e.g., by
placing the container in vacuo for a period of time. Hydration of
the film may be accomplished by adding an aqueous medium and
agitating the resulting mixture. Disruption of LMV suspensions
using sonic energy typically produces small unilamellar vesicles
(SUV) with diameters in the range of 15-50 nm. Lipid extrusion is a
technique in which a lipid suspension is forced through a
polycarbonate filter with a defined pore size to yield particles
having a diameter near the pore size of the filter used. Extrusion
through filters with 100 nm pores typically yields large,
unilamellar vesicles (LUV) with a mean diameter of 120-140 nm. In
certain embodiments, the amount of a MON described herein in the
liposome is between about 30 mol % and about 80 mol %, between
about 40 mol % and about 70 mol %, or between about 60 mol % and
about 70 mol %, inclusive. In certain embodiments, the MONs further
complexes an agent, such as a small molecule.
[0632] Liposomes and micelles may also be prepared according to
methods in the following scientific papers: Narang et al.,
"Cationic Lipids with Increased DNA Binding Affinity for Nonviral
Gene Transfer in Dividing and Nondividing Cells," Bioconjugate
Chem. 16:156-68, 2005; Hofland et al., "Formation of stable
cationic lipid/DNA complexes for gene transfer," Proc. Natl. Acad.
Sci. USA 93:7305-7309, July 1996; Byk et al., "Synthesis, Activity,
and Structure--Activity Relationship Studies of Novel Cationic
Lipids for DNA Transfer," J. Med. Chem. 41(2):224-235, 1998; Wu et
al., "Cationic Lipid Polymerization as a Novel Approach for
Constructing New DNA Delivery Agents," Bioconjugate Chem.
12:251-57, 2001; Lukyanov et al., "Micelles from lipid derivatives
of water-soluble polymers as delivery systems for poorly soluble
drugs," Advanced Drug Delivery Reviews 56:1273-1289, 2004;
Tranchant et al., "Physicochemical optimisation of plasmid delivery
by cationic lipids," J. Gene Med. 6:S24-S35, 2004; van Balen et
al., "Liposome/Water Lipophilicity: Methods, Information Content,
and Pharmaceutical Applications," Medicinal Research Rev.
24(3):299-324, 2004.
Gels
[0633] Gels are different from classical mechanics of materials, in
that the timescale associated with the imposed stress or strain can
affect the mechanical response by several orders of magnitude.
These viscoelastic characteristics of gels are significant to many
applications, and better understanding of the spatial and temporal
mechanisms which effect desirable mechanical properties will lead
to better materials designs. In gels, the timescales over which
mechanical interactions occur are highly important; materials can
have apparent fluid-like properties at long timescales yet apparent
solid-like properties at short timescales. Typically, gels possess
little long-range spatial ordering. Instead, the molecules in the
gels arrange themselves in a wide array of spatial conformations.
This spatial heterogeneity effects a corresponding temporal
heterogeneity: upon application of a stress, the material begins to
relax by deforming. Each of the local conformations relax at a
distinct timescale. The mechanical properties (e.g., viscoelastic
properties) of gels are important for the gels to be used in
various applications. For example, it has been shown that substrate
elasticity can determine mesenchymal stem cell differentiation
(Engler et al. Cell, 2006, 126, 677-689). There is a need for gels
with "designer viscoelasticity," the ability to create gels with a
specifically engineered viscoelastic spectrum. Conventional methods
for designing the mechanical properties of gels include changing
the molecular weight or molecular weight distribution of the
polymer matrix, increasing the degree of crosslinking between
polymer chains, changing the stiffness of the polymer backbone, and
changing the bulkiness of the side groups. However, these
conventional techniques alter the properties of the polymer matrix
such that they add other features which may be undesirable.
[0634] Coordination chemistry typically features bonds between
metals and ligands that are intermediate in bond-energy between
covalent bonds and non-covalent interactions (e.g., van der Waals
interactions and H-bonding). Such bonds can be reversible or
dynamic under appropriate conditions; they have been extensively
used for the formation of a class of gel
networks--metallogels--that features stimuli-responsive
properties..sup.1-32 Due to their low branch functionality and
dynamic bonds, most metallogels are soft elastic materials (storage
moduli of G'.ltoreq.20 kPa at .about.2 to 10 wt. % polymer network)
that often display viscous flow behavior at low shear strain
frequencies..sup.6,7,21,26,29 These weak mechanical properties
severely limit the possible applications of metallogels; the
desirable dynamic properties inevitably come at the expense of
structural integrity.
[0635] Recently, transition metal-organic ligand complexes have
been suggested to reinforce the mechanical properties and
self-healing nature of marine mussel adhesion fibers ("byssi")
(Harrington et al. Science, 2010, 328, 216-220; Harrington et al.
The Journal of Experimental Biology, 2007, 210, 4307-4318;
Holten-Andersen et al. Nature Materials, 2007, 6, 669-672; Lee et
al. Proceedings of the National Academy of Sciences of the United
States of America, 2006, 103, 12999-13003). Efforts have been made
to mimic the extraordinary mechanical properties of the byssi using
simplified synthetic analogs (Holten-Andersen et al. Proceedings of
the National Academy of Sciences of the United States of America,
2011, 108, 2651-2655; Holten-Andersen et al., Journal of Materials
Chemistry B, 2014, 2, 2467-2472; Lee et al. Annual Review of
Materials Research, 2011, 41, 99-132; Barrett et al. Advanced
functional materials, 2013, 23, 1111-1119; Fullenkamp et al.
Macromolecules, 2013, 46, 1167-1174). Craig et al. has reported the
formation and dynamic mechanical properties of
metallo-supramolecular networks formed by mixtures of bis-Pd(II)
and Pt(II) cross-linkers with poly(4-vinylpyridine) in DMSO. These
networks have relaxation timescales that vary across several orders
of magnitude. Also reported are that the kinetics of metal-ligand
dissociation could be used to tune the apparent mechanical
properties of a metallogel within a relevant timescale..sup.24-26
Furthermore, it has been shown that the thermodynamics of
coordination can serve as a partially complementary parameter to
tune the mechanical properties of gels..sup.26 Though manipulation
of the kinetic and thermodynamic properties of individual
metal-ligand bonds offers one way to modulate bulk properties, this
strategy is ultimately limited in terms of the magnitude of changes
that can be induced. Furthermore, it requires the design and
synthesis of an assortment of ligand architectures and/or the use
of different metals to induce changes in network behavior, which
may not be compatible with a given application.
[0636] Tetrazine derivatives are another ligand that is useful in
transition metal-ligand complexes. Interest in tetrazine reactivity
has recently resurged largely due to its use in bioconjugate and
polymer chemistry (Wollack, J. W.; Monson, B. J.; Dozier, J. K.;
Dalluge, J. J.; Poss, K.; Hilderbrand, S. A.; Distefano, M. D.
Chemical Biology & Drug Design 2014, 84, 140; Darko, A.;
Wallace, S.; Dmitrenko, O.; Machovina, M. M.; Mehl, R. A.; Chin, J.
W.; Fox, J. M. Chemical Science 2014, 5, 3770; Wu, H.; Cisneros, B.
T.; Cole, C. M.; Devaraj, N. K. Journal of the American Chemical
Society 2014, 136, 17942; Hansell, C. F.; Espeel, P.; Stamenovi ,
M. M.; Barker, I. A.; Dove, A. P.; Du Prez, F. E.; O'Reilly, R. K.
Journal of the American Chemical Society 2011, 133, 13828;
Blackman, M. L.; Royzen, M.; Fox, J. M. Journal of the American
Chemical Society 2008, 130, 13518; Cok, A. M.; Zhou, H.; Johnson,
J. A. Macromolecular Symposia 2013, 329, 108; Zhou, H.; Woo, J.;
Cok, A. M.; Wang, M.; Olsen, B. D.; Johnson, J. A. Proceedings of
the National Academy of Sciences 2012). Certain tetrazine species
are known for their binding to various metal ions; specifically,
3,6-bis(2-pyridyl)-1,2,4,5-tetrazines (bptz), has been studied for
additional purposes by several groups as ligands in self-assembled
structures. The Dunbar group reported the synthesis of molecular
triangles, squares, and pentagons using bptz and various metal ions
including Fe.sup.2+, Ni.sup.2+, and Ag.sup.+, respectively.
Additional accounts of using bptz include gold surface modification
and its use as a ligand for rhenium to use its MLCT for study in
photoinduced charge separation (Skomski, D.; Tempas, C. D.; Smith,
K. A.; Tait, S. L. Journal of the American Chemical Society 2014,
136, 9862; Li, G.; Parimal, K.; Vyas, S.; Hadad, C. M.; Flood, A.
H.; Glusac, K. D. J. Am. Chem. Soc. 2009, 131, 11656).
[0637] It has previously reported that covalent A.sub.2+B.sub.3
type end-linked polymer networks was synthesized using a tris-bptz
trifunctional crosslinker and norbornene-terminated poly(ethylene
glycol) (PEG) telechelic polymers (Hansell, C. F.; Espeel, P.;
Stamenovic, M. M.; Barker, I. A.; Dove, A. P.; Du Prez, F. E.;
O'Reilly, R. K. Journal of the American Chemical Society 2011, 133,
13828; Cok, A. M.; Zhou, H.; Johnson, J. A. Macromolecular Symposia
2013, 329, 108; Zhou, H.; Woo, J.; Cok, A. M.; Wang, M.; Olsen, B.
D.; Johnson, J. A. Proceedings of the National Academy of Sciences
2012; Zhou, H.; Johnson, J. A. Angew. Chem., Int. Ed. 2013, 52,
2235). Strained alkenes and tetrazines undergo facile
inverse-electron demand Diels-Alder reactions with the extrusion of
nitrogen, which make them useful for efficiently synthesizing
catalyst-free, two component polymer networks. Subsequent work by
Anseth and coworkers used this chemistry to construct
cytocompatible gels that could be photochemically patterned (Alge,
D. L.; Azagarsamy, M. A.; Donohue, D. F.; Anseth, K. S.
Biomacromolecules 2013, 14, 949). However, there are no known
references of bptz-metal coordination as a mode of crosslinking for
the formation of end-linked polymer networks and the applications
thereof.
[0638] A key component of polymer network structures that cannot be
readily addressed by traditional metallogels is the network branch
functionality, f, which is the average number of chains that
emanate from junctions within a network. According to the phantom
network model of rubber elasticity, the modulus of a gel increases
with f..sup.33 In traditional metallogels, the junctions are single
metal centers; f is dictated by the number of ligands that can bind
to that metal, which is typically limited to values between two and
four. Thus, metallogels are typically very soft materials, and it
is very difficult to tune f without complete redesign of the
network components.
[0639] It was envisioned that dramatic enhancements in f could be
realized if network junctions were created through metal-ligand
self-assembly into higher-order cage-like structures. Such
"suprametallogels" would retain the dynamic properties of
metallogels while potentially featuring broadly tunable branch
architectures and enhanced mechanical properties. Nature uses
hierarchical, multivalent assembly of weakly interacting species to
produce biological gels with robust mechanical properties and
dynamic behavior. Similar concepts have been adopted to increase
the mechanical stability of synthetic networks..sup.34 As
demonstrated here, programmed metallosupramolecular assembly for
gelation is attractive because it enables tuning of gel properties
over a wide range using the same metal and polymer, and very simple
ligand modifications.
[0640] Numerous examples of ligand-metal combinations are known to
provide discrete self-assembled cage-like structures..sup.35-48
Reports of Fujita and coworkers on the formation of
M.sub.12L.sub.24 spherical cages from the assembly of twenty-four
phenyl-3,5-bis-(para-pyridine) ligands and 12 Pd.sup.2+ atoms were
inspiring. In several studies, these authors have shown that these
assemblies can be synthesized in quantitative yield, that they are
robust towards a diverse range of ligand substitutions,.sup.49,50
and that they can serve as small molecule hosts and
nano-reactors..sup.36 Thus, incorporation of these supramolecular
cages as junctions within a polymer network could afford
suprametallogels with additional advantages--aside from mechanical
ones--over conventional metallogels such as the ability to
encapsulate and release species within the junction cages, or
conduct reactions in confined spaces within the gel.
[0641] Two questions were to be answered. First, if bis-pyridyl
moieties similar to those used by Fujita et al..sup.36 are appended
onto the ends of linear polymer chains, will those polymer chains
form suprametallogels in the presence of Pd.sup.2+ through the
self-assembly of the polymer chain ends? This question is
non-trivial, because gelation has the potential to dramatically
perturb the dynamics of cage self-assembly. Second, if an isomeric
bis-pyridyl ligand, one that does not generate spherical cages but
an alternative assembly, can be used to tune the network branch
functionality in a rational manner? For example, in contrast to the
defined 120.degree. bite angle of the para-pyridine isomers, the
corresponding meta isomers have infinitely many possible bite
angles between 0.degree. and 240.degree. depending on the relative
orientation of the two pyridines. Ditopic ligands with similar
geometry are known to self-assemble into M.sub.2L.sub.4
paddlewheels with several types of metal ions, including
Pd.sup.2+..sup.51-65 A 1-hydroxymethyl derivative was synthesized,
and it was confirmed that it quantitatively forms M.sub.2L.sub.4
paddlewheels in the presence of Pd.sup.2+ ions. In other words, a
small difference in macromonomer ligand structure may provide
materials with different bulk properties. Notably, this approach
stands in stark contrast to gels that are formed via pre-assembly
of metal-ligand-derived MONs that feature orthogonal groups for
subsequent crosslinking..sup.66-68 Presented here are examples of
gelation induced through metal-ligand bond formation and
concomitant metallosupramolecular assembly (e.g., induced
exclusively through metal-ligand bond formation and concomitant
metallosupramolecular assembly).
[0642] Therefore, in another aspect, the present disclosure
provides compositions that are gels or in the form of a gel (e.g.,
hydrogel), the compositions including a BCPMON and optionally an
agent described herein. The gels described herein are
suprametallogels. A BCPMON described herein and/or an adduct of a
BCPMON and an agent (supramolecule-agent adduct) may be able to
form a gel upon contacting a fluid. In certain embodiments, the
fluid is a suitable solvent described herein (e.g., water). In
certain embodiments, the BCPMON and/or supramolecule-agent adduct
form a gel at least through the complexation of ligands of Formula
(A), (C), or (B) and transition metal ions and optionally also
through other non-covalent interrelations (e.g., electrostatic
interactions, hydrophobic interactions, hydrogen bonding, van der
Waals interactions, and/or .pi.-.pi. stacking). A BCPMON and/or
supramolecule-agent adduct described herein may form a gel upon
contacting a fluid when the concentration of the BCPMON and/or
supramolecule-agent adduct in the fluid is a suitable concentration
described herein (e.g., between about 10 and about 500 millimoles
of a reactant or reagent (e.g., a ligand of Formula (A), (C), or
(B); a macromonomer of Formula (L) or (M); or a transition metal
salt) per liter of the fluid, inclusive). The structure of a gel
described herein includes the primary structure (e.g., the
structure of the MON moieties of the gel) and secondary structure
(e.g., the degree of entanglement of the BCPMONs in the gel). An
instance of the BCPMON may entangle within itself, and two or more
instances of the BCPMON may also entangle. The entangled BCPMON(s)
form a molecular network that includes cavities, which may be
filled with a fluid when the BCPMON(s) are contacted with the
fluid, and the BCPMON(s) may retain the fluid and be swelled,
rather than be dissolved, by the fluid to form a gel. A high degree
of entanglement of the BCPMONs may be beneficial for the formation
of a gel when the BCPMONs are contacted with a fluid. In certain
embodiments, the fluid comprises water, DMSO, acetonitrile, or a
mixture thereof. In certain embodiments, the fluid comprises water.
In certain embodiments, wherein the fluid is water.
[0643] Conventional gels (e.g., gels formed by swelling a
covalently cross-linked polymer with a fluid) are typically not
able to flow under a suitable stress (a suitable shear stress) and
to self-heal when damaged. The gels described herein are
advantageous over the conventional gels at least in that the gels
described herein are able to flow under a suitable stress and to
self-heal when damaged. While a conventional gel is usually
thermally irreversible, the gels described herein are
thermoreversible. A change in physical and/or chemical conditions
(e.g., stress, temperature, and/or concentration) from a first
condition to a second condition may result in a change in the
degree of gelation of a gel described herein from a first degree of
gelation to a second degree of gelation. A change in physical
and/or chemical conditions (e.g., stress, temperature, and/or
concentration) from the second condition to the first condition may
result in a change in the degree of gelation of a gel described
herein from the second degree of gelation to the first degree of
gelation. The molecular network of a gel described herein may
reversibly deform at least through weakening or strengthening, or
breaking or reforming, the coordination bonds between the ligands
of Formula (A), (C), or (B) and the transition metal ions by
changing physical and/or chemical conditions. In contrast, the
covalent bonds in a conventional gel typically cannot be reversibly
weakened or strengthened, or broken or reformed, by changing
physical and/or chemical conditions. The aggregation of the
molecules in a gel described herein is more dynamic, compared to
the aggregation of the molecules in a conventional gel, and the
more dynamic aggregation in a gel described herein is at least due
to the non-covalent interactions between the molecules therein.
Conventional gels typically cannot be easily characterized using
spectroscopic techniques. In contrast, the gels described herein
allow facile characterizations using readily available
spectroscopic techniques (e.g., UV-vis absorption spectroscopy and
Raman spectroscopy) under various conditions. Combination of
chemical spectroscopy with mechanical tests will then beget spatial
structure-temporal structure-mechanical property relationships;
this allows for shape design criteria for engineering the
mechanical properties of gels (vis-a-vis modulating the modes of
the relaxation spectrum).
[0644] The gels described herein are also advantageous over
conventional MONs (e.g., nanoparticles without the block-co-polymer
moieties (-L-(R).sub.p-(G).sub.q-(R).sub.u-(G).sub.v-E)).
Individual instances of a conventional MON are not covalently
linked to each other, and therefore, the conventional MONs
typically lack robustness and/or storage modulus. The covalent
bonding between the individual MONs in a gel described herein is
stronger than the non-covalent interactions, if any, between the
individual MONs in conventional MONs. Therefore, compared to
conventional MONs, the gels described herein show higher robustness
and/or higher storage modulus.
[0645] The BCPMONs and compositions (e.g., gels) may also be able
to absorb a large amount of a fluid (e.g., absorb at least 100
times by weight of the fluid, compared to the weight of the BCPMON
or the dry weight of the composition (weight of the composition
minus the weight of the fluid included in the composition) and,
therefore, may be useful as super-absorbent materials.
[0646] In certain embodiments, each instance of the BCPMON is the
same. In certain embodiments, two or more instances of the BCPMON
are different from each other. In certain embodiments, each
instance of the ligand of Formula (A) is the same. In certain
embodiments, two or more instances of the ligand of Formula (A) are
different from each other. In certain embodiments, each instance of
the ligand of Formula (B) is the same. In certain embodiments, two
or more instances of the ligand of Formula (B) are different from
each other. In certain embodiments, each instance of the transition
metal ion or transition metal salt is the same. In certain
embodiments, two or more instances of the transition metal ion or
transition metal salt are different from each other. In certain
embodiments, at least an instance of G of a first instance of the
BCPMON, and at least an instance of G of a second instance of the
BCPMON are associated by non-covalent interactions. In certain
embodiments, the non-covalent interactions are reversible. In
certain embodiments, the non-covalent interactions are reversible
at different temperatures.
Kits
[0647] Also described herein are kits (e.g., packs). The kits
provided may comprise (1) a macromonomer, BCPMON, thermoplastic
elastomer, gel, or composition described herein; and (2) a
container (e.g., a vial, ampule, bottle, syringe, and/or dispenser
package, or other suitable container). In certain embodiments, the
macromonomer, BCPMON, thermoplastic elastomer, gel, or composition
is included in the container. In some embodiments, a kit described
herein further includes a second container comprising an excipient.
In some embodiments, the macromonomer, BCPMON, thermoplastic
elastomer, gel, or composition provided in the first container and
the excipient provided in the second container are combined to form
one unit dosage form.
[0648] In certain embodiments, the kits described herein are useful
for delivering an agent to a subject, tissue, or cell. In certain
embodiments, the kits are useful for delivering an agent to a
target tissue described herein. In certain embodiments, the kits
are useful for treating a disease described herein. In certain
embodiments, the kits are useful for preventing a disease described
herein.
[0649] In certain embodiments, the described kits further include
instructions for administering a macromonomer, BCPMON,
thermoplastic elastomer, gel, or composition described herein. The
kits may also include information as required by a regulatory
agency such as the U.S. Food and Drug Administration (FDA). In
certain embodiments, the information included in the kits is
prescribing information. In certain embodiments, the kits,
including the instructions, provide for delivering an agent
described herein to a subject, tissue, or cell. In certain
embodiments, the kits, including the instructions, provide for
treating a disease described herein. In certain embodiments, the
kits, including the instructions, provide for preventing a disease
described herein. The kit described herein may include one or more
agents described herein as a separate composition.
Methods of Preparation and Products Prepared by Methods of
Preparation
[0650] Another aspect of the present disclosure relates to methods
of preparing a BCPMON described herein comprising complexing a
macromonomer described herein with a transition metal salt.
[0651] Another aspect of the present disclosure relates to methods
of preparing a thermoplastic elastomer described herein comprising
annealing two or more instances of a BCPMON described herein.
[0652] Another aspect of the present disclosure relates to methods
of preparing a gel described herein comprising contacting two or
more instances of a BCPMON described herein with a fluid. In
certain embodiments, the method of preparing a gel further
comprises annealing the product formed by contacting the two or
more instances of the BCPMON with the fluid.
[0653] Another aspect of the present disclosure relates to methods
of preparing a composition described herein comprising complexing a
macromonomer described herein with a transition metal salt in the
presence of an agent. In certain embodiments, the method of
preparing a composition further comprises annealing the product
formed by complexing the macromonomer with the transition metal
salt in the presence of the agent. In certain embodiments, two or
more products formed by complexing the macromonomer with the
transition metal salt in the presence of the agent are
different.
[0654] Another aspect of the present disclosure relates to
thermoplastic elastomers prepared by a method described herein.
[0655] Another aspect of the present disclosure relates to gels
prepared by a method described herein.
[0656] In certain embodiments, each instance of the transition
metal ion or transition metal salt is the same. In certain
embodiments, two or more instances of the transition metal ion or
transition metal salt are different from each other.
Methods of Treatment and Uses
[0657] One of the major problems in the development of formulations
of pharmaceutical agents (e.g., anti-cancer agents) is the delivery
of the pharmaceutical agents with adequately high bioavailability
for therapeutic intentions. Using conventional delivery techniques,
many pharmaceutical agents cannot be delivered effectively to the
target tissues or target cells. Gels, such as hydrogels, have
emerged as an important class of materials for biomedical
applications due to their unique properties that bridge the gap
between solid and liquid states. The gels described herein are
advantageous over conventional gels that typically include a
covalently cross-linked polymer network at least because the
molecular network of a gel described herein is formed at least by
non-covalent interactions, such as complexation of a ligand and a
transition metal ion, and thus is thermoreversible, able to flow
(e.g., under a high shear stress), and able to self-heal when
damaged. An agent may be encapsulated in a gel described herein
(e.g., encapsulated in a MON moiety of a BCPMON of the gel) and is
delivered to a tissue or cell (e.g., a target tissue or target
cell). The gel may dissociate in the tissue or cell to release the
agent to the tissue or cell. In certain embodiments, a MON moiety
of a BCPMON of the gel dissociates (e.g., by breaking the
coordination bonds between (1) the ligands of Formula (A), (C), or
(B) or macromonomers of Formula (L) or (M) and (2) the transition
metal ions) to release the agent that was encapsulated in the MON
moiety before the dissociation. The gels described herein may also
be advantageous over conventional nanoparticles at least because
the gels described herein may be more robust and may have higher
storage modulus than the conventional nanoparticles.
[0658] In another aspect, the present disclosure provides methods
of delivering an agent described herein (e.g., small molecule) to a
subject, tissue, or cell. In certain embodiments, described herein
are methods of delivering the agent to a target tissue or target
cell described herein. In certain embodiments, described herein are
methods of selectively delivering the agent to a target tissue,
compared to a non-target tissue. In certain embodiments, described
herein are methods of selectively delivering the agent to a target
cell, compared to a non-target cell. In certain embodiments, the
agent is delivered into the subject, tissue, or cell by the methods
described herein. In certain embodiments, the agent is selectively
delivered into the target tissue or target cell by the methods
described herein, compared to a non-target tissue or non-target
cell, respectively.
[0659] Another aspect of the present disclosure relates to methods
of increasing the delivery of an agent to a subject, tissue, or
cell. In certain embodiments, the delivery of the agent to the
subject, tissue, or cell is increased by a method described herein.
In certain embodiments, the delivery of the agent to the subject,
tissue, or cell by a method described herein is increased compared
to the delivery of the agent to the subject, tissue, or cell by a
control method that does not involve a composition described
herein.
[0660] In another aspect, the present disclosure provides methods
of treating a disease described herein in a subject in need
thereof.
[0661] In another aspect, the present disclosure provides methods
of preventing a disease described herein in a subject in need
thereof.
[0662] In certain embodiments, a disease described herein is a
genetic disease. In certain embodiments, the disease is a
proliferative disease. In certain embodiments, the disease is
cancer. In certain embodiments, the disease is a benign neoplasm.
In certain embodiments, the disease is pathological angiogenesis.
In certain embodiments, the disease is an inflammatory disease. In
certain embodiments, the disease is an autoimmune disease. In
certain embodiments, the disease is a hematological disease. In
certain embodiments, the disease is a neurological disease. In
certain embodiments, the disease is a gastrointestinal disease. In
certain embodiments, the disease is a liver disease. In certain
embodiments, the disease is a spleen disease. In certain
embodiments, the disease is a respiratory disease. In certain
embodiments, the disease is a lung disease. In certain embodiments,
the disease is a painful condition. In certain embodiments, the
painful condition is inflammatory pain. In certain embodiments, the
painful condition is associated with an inflammatory disorder
and/or an autoimmune disorder. In certain embodiments, the disease
is a genitourinary disease. In certain embodiments, the disease is
a musculoskeletal condition. In certain embodiments, the disease is
an infectious disease. In certain embodiments, the disease is a
psychiatric disorder. In certain embodiments, the disease is a
metabolic disorder. In certain embodiments, the disease is hepatic
carcinoma. In certain embodiments, the disease is
hypercholesterolemia. In certain embodiments, the disease is
refractory anemia. In certain embodiments, the disease is familial
amyloid neuropathy.
[0663] Another aspect of the present disclosure relates to methods
of genetically engineering a subject. In certain embodiments, the
subject is genetically engineered to increase the growth of the
subject. In certain embodiments, the subject is genetically
engineered to increase the subject's resistance to pathogenic
organisms and/or microorganisms (e.g., viruses, bacteria, fungi,
protozoa, and parasites).
[0664] In certain embodiments, a method described herein includes
administering to the subject a composition described herein. In
certain embodiments, a method described herein includes
administering to the subject an effective amount of a composition
described herein.
[0665] In certain embodiments, a method described herein includes
contacting the tissue with a composition described herein. In
certain embodiments, a method described herein includes contacting
the tissue with an effective amount of a composition described
herein.
[0666] In certain embodiments, a method described herein includes
contacting the cell with a composition described herein. In certain
embodiments, a method described herein includes contacting the cell
with an effective amount of a composition described herein.
[0667] In certain embodiments, a subject described herein is a
human. In certain embodiments, the subject is an animal. In certain
embodiments, the subject is a non-human animal. The animal may be
of either sex and may be at any stage of development. In certain
embodiments, the subject is a fish. In certain embodiments, the
subject is a mammal. In certain embodiments, the subject is a
non-human mammal. In certain embodiments, the subject is a
domesticated animal, such as a dog, cat, cow, pig, horse, sheep, or
goat. In certain embodiments, the subject is a companion animal
such as a dog or cat. In certain embodiments, the subject is a
livestock animal such as a cow, pig, horse, sheep, or goat. In
certain embodiments, the subject is a zoo animal. In another
embodiment, the subject is a research animal such as a rodent
(e.g., mouse, rat), dog, pig, or non-human primate. In certain
embodiments, the animal is a genetically engineered animal. In
certain embodiments, the animal is a transgenic animal. In certain
embodiments, the subject is a human with a disease described
herein. In certain embodiments, the subject is a human suspected of
having a disease described. In certain embodiments, the subject is
a human at risk of developing a disease described herein.
[0668] In certain embodiments, a cell described herein is in vivo.
In certain embodiments, a cell described herein is in vitro.
[0669] Another aspect of the present disclosure relates to uses of
a MON described herein in a method described herein (e.g., uses for
delivering an agent to a subject, tissue, or cell; uses for
treating a disease in a subject in need thereof; and uses for
preventing a disease in a subject).
[0670] Another aspect of the present disclosure relates to uses of
a BCPMON described herein in a method described herein (e.g., uses
for delivering an agent to a subject, tissue, or cell; uses for
treating a disease in a subject in need thereof; and uses for
preventing a disease in a subject).
[0671] Another aspect of the present disclosure relates to uses of
a composition (e.g., gel) described herein in a method described
herein (e.g., uses for delivering an agent to a subject, tissue, or
cell; uses for treating a disease in a subject in need thereof; and
uses for preventing a disease in a subject).
REFERENCES
[0672] 1 Xing, B., Choi, M.-F. & Xu, B. A stable metal
coordination polymer gel based on a calix[4]arene and its "uptake"
of non-ionic organic molecules from the aqueous phase. Chemical
Communications, 362-363, doi: 10.1039/B 111245G (2002). [0673] 2 J.
H. Hafkamp, R. et al. Organogel formation and molecular imprinting
by functionalized gluconamides and their metal complexes. Chemical
Communications, 545-546, doi:10.1039/A608266A (1997). [0674] 3
Xing, B., Choi, M.-F., Zhou, Z. & Xu, B. Spontaneous Enrichment
of Organic Molecules from Aqueous and Gas Phases into a Stable
Metallogel. Langmuir 18, 9654-9658, doi:10.1021/1a0256580 (2002).
[0675] 4 Xing, B., Choi, M.-F. & Xu, B. Design of Coordination
Polymer Gels as Stable Catalytic Systems. Chemistry--A European
Journal 8, 5028-5032,
doi:10.1002/1521-3765(20021104)8:21<5028:AID-CHEM5028>3.0.CO;
2-1 (2002). [0676] 5 Westhaus, E. & Messersmith, P. B.
Triggered release of calcium from lipid vesicles: a bioinspired
strategy for rapid gelation of polysaccharide and protein
hydrogels. Biomaterials 22, 453-462, doi:
dx.doi.org/10.1016/S0142-9612(00)00200-3 (2001). [0677] 6
Fullenkamp, D. E., He, L., Barrett, D. G., Burghardt, W. R. &
Messersmith, P. B. Mussel-Inspired Histidine-Based Transient
Network Metal Coordination Hydrogels. Macromolecules 46, 1167-1174,
doi: 10.1021/ma301791n (2013). [0678] 7 Holten-Andersen, N. et al.
pH-induced metal-ligand cross-links inspired by mussel yield
self-healing polymer networks with near-covalent elastic moduli.
Proceedings of the National Academy of Sciences 108, 2651-2655,
doi:10.1073/pnas.1015862108 (2011). [0679] 8 Holten-Andersen, N. et
al. Metal-coordination: using one of nature's tricks to control
soft material mechanics. Journal of Materials Chemistry B 2,
2467-2472, doi:10.1039/C3TB21374A (2014). [0680] 9 Harrington, M.
J., Masic, A., Holten-Andersen, N., Waite, J. H. & Fratzl, P.
Iron-Clad Fibers: A Metal-Based Biological Strategy for Hard
Flexible Coatings. Science 328, 216-220, doi: 10.1126/science.
1181044 (2010). [0681] Zhao, Y., Beck, J. B., Rowan, S. J. &
Jamieson, A. M. Rheological Behavior of Shear-Responsive
Metallo-Supramolecular Gels. Macromolecules 37, 3529-3531, doi:
10.1021/ma0497005 (2004). [0682] 11 Weng, W., Beck, J. B.,
Jamieson, A. M. & Rowan, S. J. Understanding the Mechanism of
Gelation and Stimuli-Responsive Nature of a Class of
Metallo-Supramolecular Gels. Journal of the American Chemical
Society 128, 11663-11672, doi: 10.1021/ja063408q (2006). [0683] 12
Weng, W., Jamieson, A. M. & Rowan, S. J. Structural origin of
the thixotropic behavior of a class of metallosupramolecular gels.
Tetrahedron 63, 7419-7431, doi:
dx.doi.org/10.1016/j.tet.2007.03.119 (2007). [0684] 13 Weng, W.,
Li, Z., Jamieson, A. M. & Rowan, S. J. Control of Gel
Morphology and Properties of a Class of Metallo-Supramolecular
Polymers by Good/Poor Solvent Environments. Macromolecules 42,
236-246, doi: 10.1021/ma801046w (2008). [0685] 14 Weng, W., Li, Z.,
Jamieson, A. M. & Rowan, S. J. Effect of monomer structure on
the gelation of a class of metallo-supramolecular polymers. Soft
Matter 5, 4647-4657, doi:10.1039/B911166B (2009). [0686] Beck, J.
B. & Rowan, S. J. Multistimuli, Multiresponsive
Metallo-Supramolecular Polymers. Journal of the American Chemical
Society 125, 13922-13923, doi: 10.1021/ja038521k (2003). [0687] 16
Rowan, S. J. & Beck, J. B. Metal-ligand induced supramolecular
polymerization: A route to responsive materials. Faraday
Discussions 128, 43-53, doi:10.1039/B403135K (2005). [0688] 17
Burnworth, M., Mendez, J. D., Schroeter, M., Rowan, S. J. &
Weder, C. Decoupling Optical Properties in Metallo-Supramolecular
Poly(p-phenylene ethynylene)s. Macromolecules 41, 2157-2163, doi:
10.1021/ma702712e (2008). [0689] 18 McKenzie, B. M. & Rowan, S.
J. in Molecular Recognition and Polymers 157-178 (John Wiley &
Sons, Inc., 2008). [0690] 19 Buerkle, L. E. & Rowan, S. J.
Supramolecular gels formed from multi-component low molecular
weight species. Chemical Society Reviews 41, 6089-6102, doi:
10.1039/C2CS35106D (2012). [0691] 20 Xu, D. & Craig, S. L.
Scaling Laws in Supramolecular Polymer Networks. Macromolecules 44,
5465-5472, doi: 10.1021/ma200096s (2011). [0692] 21 Xu, D. &
Craig, S. L. Strain Hardening and Strain Softening of Reversibly
Cross-Linked Supramolecular Polymer Networks. Macromolecules 44,
7478-7488, doi: 10.1021/ma201386t (2011). [0693] 22 Xu, D., Hawk,
J. L., Loveless, D. M., Jeon, S. L. & Craig, S. L. Mechanism of
Shear Thickening in Reversibly Cross-Linked Supramolecular Polymer
Networks. Macromolecules 43, 3556-3565, doi: 10.1021/ma100093b
(2010). [0694] 23 Loveless, D. M., Jeon, S. L. & Craig, S. L.
Chemoresponsive viscosity switching of a metallo-supramolecular
polymer network near the percolation threshold. Journal of
Materials Chemistry 17, 56-61, doi:10.1039/B614026B (2007). [0695]
24 Yount, W. C., Loveless, D. M. & Craig, S. L. Small-Molecule
Dynamics and Mechanisms Underlying the Macroscopic Mechanical
Properties of Coordinatively Cross-Linked Polymer Networks. Journal
of the American Chemical Society 127, 14488-14496, doi:
10.1021/ja054298a (2005). [0696] 25 Yount, W. C., Loveless, D. M.
& Craig, S. L. Strong Means Slow: Dynamic Contributions to the
Bulk Mechanical Properties of Supramolecular Networks. Angewandte
Chemie International Edition 44, 2746-2748, doi:
10.1002/anie.200500026 (2005). [0697] 26 Loveless, D. M., Jeon, S.
L. & Craig, S. L. Rational Control of Viscoelastic Properties
in Multicomponent Associative Polymer Networks. Macromolecules 38,
10171-10177, doi:10.1021/ma0518611 (2005). [0698] 27 Kean, Z. S. et
al. Increasing the Maximum Achievable Strain of a Covalent Polymer
Gel Through the Addition of Mechanically Invisible Cross-Links.
Adv. Mater. (Weinheim, Ger.), n/a-n/a, doi:10.1002/adma.201401570
(2014). [0699] 28 Nair, K. P., Breedveld, V. & Weck, M.
Modulating mechanical properties of self-assembled polymer networks
by multi-functional complementary hydrogen bonding. Soft Matter 7,
553-559, doi: 10.1039/C0SM00795A (2011). [0700] 29 Nair, K. P.,
Breedveld, V. & Weck, M. Multiresponsive Reversible Polymer
Networks Based on Hydrogen Bonding and Metal Coordination.
Macromolecules 44, 3346-3357, doi:10.1021/ma102462y (2011). [0701]
30 Hackelbusch, S., Rossow, T., van Assenbergh, P. & Seiffert,
S. Chain Dynamics in Supramolecular Polymer Networks.
Macromolecules 46, 6273-6286, doi: 10.1021/ma4003648 (2013). [0702]
31 Hackelbusch, S., Rossow, T., Becker, H. & Seiffert, S.
Multiresponsive Polymer Hydrogels by Orthogonal Supramolecular
Chain Cross-Linking. Macromolecules 47, 4028-4036,
doi:10.1021/ma5008573 (2014). [0703] 32 Zhang, Y. et al. Active
Cross-Linkers that Lead to Active Gels. Angewandte Chemie
International Edition 52, 11494-11498, doi: 10.1002/anie.201304437
(2013). [0704] 33 Rubinstein, M. & Colby, R. Polymers Physics.
(Oxford, 2003). [0705] 34 Cordier, P., Tournilhac, F.,
Soulie-Ziakovic, C. & Leibler, L. Self-healing and
thermoreversible rubber from supramolecular assembly. Nature 451,
977-980, doi:
www.nature.com/nature/journal/v451/n7181/suppinfo/nature06669_S1.html
(2008). [0706] 35 Sun, W.-Y., Yoshizawa, M., Kusukawa, T. &
Fujita, M. Multicomponent metal-ligand self-assembly. Current
Opinion in Chemical Biology 6, 757-764,
doi:_dx.doi.org/10.1016/S1367-5931(02)00358-7 (2002). [0707] 36
Harris, K., Fujita, D. & Fujita, M. Giant hollow MnL2n
spherical complexes: structure, functionalisation and applications.
Chemical Communications 49, 6703-6712, doi:10.1039/C3CC43191F
(2013). [0708] 37 Leininger, S., Olenyuk, B. & Stang, P. J.
Self-Assembly of Discrete Cyclic Nanostructures Mediated by
Transition Metals. Chem. Rev. (Washington, D.C., U. S.) 100,
853-908, doi:10.1021/cr9601324 (2000). [0709] 38 Meyer, C. D. et
al. The Dynamic Chemistry of Molecular Borromean Rings and Solomon
Knots. Chemistry--A European Journal 16, 12570-12581, doi:
10.1002/chem.201001806 (2010). [0710] 39 Forgan, R. S., Sauvage,
J.-P. & Stoddart, J. F. Chemical Topology: Complex Molecular
Knots, Links, and Entanglements. Chem. Rev. (Washington, D.C., U.
S.) 111, 5434-5464, doi: 10.1021/cr200034u (2011). [0711] 40
Chambron, J.-C. & Sauvage, J.-P. Topologically complex
molecules obtained by transition metal templation: it is the
presentation that determines the synthesis strategy. New Journal of
Chemistry 37, 49-57, doi: 10.1039/C2NJ40555E (2013). [0712] 41
Ronson, T. K., Zarra, S., Black, S. P. & Nitschke, J. R.
Metal-organic container molecules through subcomponent
self-assembly. Chemical Communications 49, 2476-2490,
doi:10.1039/C2CC36363A (2013). [0713] 42 Smulders, M. M. J.,
Riddell, I. A., Browne, C. & Nitschke, J. R. Building on
architectural principles for three-dimensional
metallosupramolecular construction. Chemical Society Reviews 42,
1728-1754, doi: 10.1039/C2CS35254K (2013). [0714] 43 Castilla, A.
M., Ramsay, W. J. & Nitschke, J. R. Stereochemistry in
Subcomponent Self-Assembly. Accounts of Chemical Research 47,
2063-2073, doi: 10.1021/ar5000924 (2014). [0715] 44
Campos-Fernindez, C. S., Clerac, R. & Dunbar, K. R. A One-Pot,
High-Yield Synthesis of a Paramagnetic Nickel Square from Divergent
Precursors by Anion Template Assembly. Angewandte Chemie
International Edition 38, 3477-3479, doi: 10.1002/(SICI)
1521-3773(19991203)38:23<3477::AID-ANIE3477>3.0.CO; 2-P
(1999). [0716] 45 Campos-Fernindez, C. S., Clerac, R., Koomen, J.
M., Russell, D. H. & Dunbar, K. R. Fine-Tuning the Ring-Size of
Metallacyclophanes: A Rational Approach to Molecular Pentagons.
Journal of the American Chemical Society 123, 773-774, doi:
10.1021/ja002960r (2001). [0717] 46 Chifotides, H. T. & Dunbar,
K. R. Anion-.pi. Interactions in Supramolecular Architectures.
Accounts of Chemical Research 46, 894-906, doi:10.1021/ar300251k
(2013). [0718] 47 Holliday, B. J. & Mirkin, C. A. Strategies
for the Construction of Supramolecular Compounds through
Coordination Chemistry. Angewandte Chemie International Edition 40,
2022-2043,
doi:10.1002/1521-3773(20010601)40:11<2022::AID-ANIE2022>3.0.CO;
2-D (2001). [0719] 48 Yoshizawa, M. & Klosterman, J. K.
Molecular architectures of multi-anthracene assemblies. Chemical
Society Reviews 43, 1885-1898, doi: 10.1039/C3CS60315F (2014).
[0720] 49 Sun, Q.-F. et al. Self-Assembled M24L48 Polyhedra and
Their Sharp Structural Switch upon Subtle Ligand Variation. Science
(Washington, D.C., U. S.) 328, 1144-1147, doi: 10.1126/science.
1188605 (2010). [0721] 50 Tominaga, M. et al. Finite, spherical
coordination networks that self-organize from 36 small components.
Angew. Chem., Int. Ed. 43, 5621-5625, doi:10.1002/anie.200461422
(2004). [0722] 51 Chand, D. K., Biradha, K. & Fujita, M.
Self-assembly of a novel macrotricyclic Pd( ) metallocage
encapsulating a nitrate ion. Chemical Communications, 1652-1653,
doi: 10.1039/B 104853H (2001). [0723] 52 Owens, T. D., Hollander,
F. J., Oliver, A. G. & Ellman, J. A. Synthesis, Utility, and
Structure of Novel Bis(sulfinyl)imidoamidine Ligands for Asymmetric
Lewis Acid Catalysis. Journal of the American Chemical Society 123,
1539-1540, doi: 10.1021/ja005635c (2001). [0724] 53 Su, C.-Y., Cai,
Y.-P., Chen, C.-L., Zhang, H.-X. & Kang, B.-S.
Coordination-directed assembly of trigonal and tetragonal molecular
boxes encapsulating anionic guests. Journal of the Chemical
Society, Dalton Transactions, 359-361, doi:10.1039/B0101180 (2001).
[0725] 54 Liu, Z.-M. et al. Assembly of Trigonal and Tetragonal
Prismatic Cages from Octahedral Metal Ions and a Flexible Molecular
Clip. Inorganic Chemistry 46, 5814-5816, doi:
10.1021/ic062270+(2007). [0726] 55 Desmarets, C., Policar, C.,
Chamoreau, L.-M. & Amouri, H. Design, Self-Assembly, and
Molecular Structures of 3D Copper(II) Capsules Templated by BF4-
Guest Anions. European Journal of Inorganic Chemistry 2009,
4396-4400, doi: 10.1002/ejic.200900606 (2009). [0727] 56 Liu, H.-K.
et al. Discrete M2L2 metallacycle and M2L4 cage frameworks and
anion competitive reactions of Cu2L4 type receptor. Inorganic
Chemistry Communications 12, 457-460, doi:
dx.doi.org/10.1016/j.inoche.2009.03.017 (2009). [0728] 57 Liao, P.
et al. Two-component control of guest binding in a self-assembled
cage molecule. Chemical Communications 46, 4932-4934, doi:
10.1039/C0CC00234H (2010). [0729] 58 Kishi, N., Li, Z., Yoza, K.,
Akita, M. & Yoshizawa, M. An M2L4 Molecular Capsule with an
Anthracene Shell: Encapsulation of Large Guests up to 1 nm. Journal
of the American Chemical Society 133, 11438-11441, doi:
10.1021/ja2037029 (2011). [0730] 59 Li, Z., Kishi, N., Hasegawa,
K., Akita, M. & Yoshizawa, M. Highly fluorescent M2L4 molecular
capsules with anthracene shells. Chemical Communications 47,
8605-8607, doi:10.1039/C1CC12946E (2011). [0731] 60 Li, Z., Kishi,
N., Yoza, K., Akita, M. & Yoshizawa, M. Isostructural M2L4
Molecular Capsules with Anthracene Shells: Synthesis, Crystal
Structures, and Fluorescent Properties. Chemistry--A European
Journal 18, 8358-8365, doi:10.1002/chem.201200155 (2012). [0732] 61
Barbour, L. J., Orr, G. W. & Atwood, J. L. An intermolecular
(H2O).sub.10 cluster in a solid-state supramolecular complex.
Nature 393, 671-673, doi:
www.nature.com/nature/journal/v393/n6686/suppinfo/393671a0_S1.html
(1998). [0733] 62 Yue, N. L. S., Eisler, D. J., Jennings, M. C.
& Puddephatt, R. J. Macrocyclic and Lantern Complexes of
Palladium(II) with Bis(amidopyridine) Ligands: Synthesis,
Structure, and Host-Guest Chemistry. Inorganic Chemistry 43,
7671-7681, doi: 10.1021/ic048893+(2004). [0734] 63 Amouri, H. et
al. Host-Guest Interactions: Design Strategy and Structure of an
Unusual Cobalt Cage That Encapsulates a Tetrafluoroborate Anion.
Angewandte Chemie International Edition 44, 4543-4546, doi:
10.1002/anie.200500786 (2005). [0735] 64 Clever, G. H., Tashiro, S.
& Shionoya, M. Inclusion of Anionic Guests inside a Molecular
Cage with Palladium(II) Centers as Electrostatic Anchors.
Angewandte Chemie International Edition 48, 7010-7012, doi:
10.1002/anie.200902717 (2009). [0736] 65 Hirakawa, T. et al.
Removal of Perchlorate Anion from an Aqueous Solution by
Encapsulation in an Anion-templated Self-assembled Molecular
Capsule. Chemistry Letters 38, 290-291, doi: 10.1246/cl.2009.290
(2009). [0737] 66 Yan, X. et al. Responsive Supramolecular Polymer
Metallogel Constructed by Orthogonal Coordination-Driven
Self-Assembly and Host/Guest Interactions. Journal of the American
Chemical Society 136, 4460-4463, doi: 10.1021/ja412249k (2014).
[0738] 67 Yan, X. et al. Hierarchical Self-Assembly: Well-Defined
Supramolecular Nanostructures and Metallohydrogels via Amphiphilic
Discrete Organoplatinum(II) Metallacycles. Journal of the American
Chemical Society 135, 14036-14039, doi: 10.1021/ja406877b (2013).
[0739] 68 Yan, X. et al. Supramolecular polymers with tunable
topologies via hierarchical coordination-driven self-assembly and
hydrogen bonding interfaces. Proceedings of the National Academy of
Sciences 110, 15585-15590, doi:10.1073/pnas.1307472110 (2013).
[0740] 69 Crystals were obtained by vapor diffusion of ethyl
acetate into DMSO-d6 at 23
.degree. C. [0741] 70 The chemical shifts and symmetric nature of
the broad resonances mapped well onto the solution .sup.1H NMR
spectra of the L-spheres and soluble polymer network fragments
derived from B-3. [0742] 71 Yoneya, M., Tsuzuki, S., Yamaguchi, T.,
Sato, S. & Fujita, M. Coordination-Directed Self-Assembly of
M12L24 Nanocage: Effects of Kinetic Trapping on the Assembly
Process. ACS Nano 8, 1290-1296, doi: 10.1021/nn404595j (2014).
[0743] 72 Yoneya, M., Yamaguchi, T., Sato, S. & Fujita, M.
Simulation of Metal-Ligand Self-Assembly into Spherical Complex
M6L8. J. Am. Chem. Soc. 134, 14401-14407, doi:10.1021/ja303542r
(2012). [0744] 73 Greater junction functionality translates into
smaller .mu. for the same .nu. in the phantom network model
equation G'phantom=RT(.nu.-.mu.).phi.-1/3.
EXAMPLES
[0745] In order that the invention described herein may be more
fully understood, the following examples are set forth. The
synthetic and biological examples described herein are offered to
illustrate the present disclosure and are not to be construed in
any way as limiting their scope.
Example 1. Preparation and Characterization of BCPMONs of Formula
(A) or (B)
[0746] For the realization of exemplary BCPMONs, poly(methyl
methacrylate)-block-poly(n-butyl acrylate) (PMMA-b-PBA, or
PMMA-PBA) bearing a pyridyl ligand at the chain end was used.
PMMA-PBA is known to phase separate in the bulk state as well as in
suitable solvents..sup.56-57 The ligands of choice are shown in
FIG. 1B. In the presence of Pd ions, these ligands form
Pd.sub.xL.sub.y complexes with different geometries: ligand L1
forms a square planar ML.sub.4 complex (this ligand may serve as a
control for comparison to BCPMONs), while ligands L2 and L3 are
structural isomers of meta- and para-bispyridine that assemble into
M.sub.2L.sub.4 paddlewheel and M.sub.12L.sub.24 Fujita sphere MONs,
respectively. Schematics for these complexes are shown in FIG.
1C.
BCP Synthesis
[0747] The BCPs were synthesized via atom transfer radical
polymerization (ATRP), followed by post-polymerization
functionalization (FIG. 2A). Using Ethyl a-bromophenylacetate
(EBPA) as the initiator, the PMMA block could be synthesized with
low dispersities (D=1.05-1.10) and controlled molecular
weights..sup.58 The obtained PMMA then served as a macro-initiator
for the synthesis of PMMA-PBA through chain extension. To install
the desired ligand on the PBA chain end, a nucleophilic
substitution reaction was used in which the appropriate pyridyl
phenol ligand displaced the polymer chain end bromide to yield an
ether product. The functionalized polymers were purified by silica
gel chromatography. .sup.1H nuclear magnetic resonance spectroscopy
(.sup.1H NMR) confirmed the presence of protons from both the EBPA
initiator and the bispyridine chain end, as labeled in FIGS. 2B to
2C. The integration of characteristic peaks for all three
macro-ligands matches the chemical structures, which suggests a
high degree (>95%) of chain-end functionalization (FIG. 7).
Apart from the difference in the ligands, BCPs of different
molecular weights and block volume fractions were synthesized for
comparison; detailed characterization data for all polymers studied
are listed in Table 1. For nomenclature, PMMA.sub.4k-PBA.sub.19k-L1
stands for BCPs with a number-average molecular weight of 4k Da and
19k Da for each block and ligand L1 as the chain end (also
abbreviated as -L1 in the same context).
TABLE-US-00001 TABLE 1 Characterization data for BCPs.
.sup.aPolymer .sup.bM.sub.n .sup.cN.sub.PMMA .sup.df.sub.PMMA
.sup.cN.sub.PBA .sup.df.sub.PBA PMMA.sub.4k-PBA.sub.19k 22.9k 1.14
39 16.4 147 83.6 PMMA.sub.8k-PBA.sub.27k 34.1k 1.07 82 23.1 221
76.9 PMMA.sub.8k-PBA.sub.48k 52.1k 1.09 82 14.8 385 85.2
.sup.aNumber-average molecular weight (M.sub.n) and .sup.cdegree of
polymerization (N) determined by .sup.1H NMR. .sup.bM.sub.n
measured by GPC (solvent, THF). .sup.cVolumne fraction (f) is
calculated based on N and the density of PMMA and PBA.
Metal-Coordination Driven MON Assembly
[0748] When palladium ions (Pd.sup.2+) are introduced to a solution
of PMMA-PBA-L in acetonitrile, Pd-pyridine metal-coordination
occurs rapidly to give poorly defined coordination polymer
networks. However, upon thermal annealing, the BCP-bound ligands
and Pd.sup.2+ ions assemble into the clusters shown schematically
in FIG. 1C. .sup.1H NMR was used to study the assembly process as
well as the differences between polymers bearing various chain
ends. PMMA.sub.4k-PBA.sub.19k polymers are used as examples. The
.sup.1H NMR spectra for meta-bispyridyl L2 functionalized polymer
(PMMA.sub.4k-PBA.sub.19k-L2) are shown in FIG. 2B. When Pd.sup.2+
is added, most of the peaks corresponding to the ligand shift
downfield. In particular, the peaks for the a pyridyl protons
(labeled as a and b in FIG. 2B) shift from 8.9 to 10.5 ppm, and 8.6
to 9.4 ppm, respectively. The new chemical shifts agree with those
obtained from a model study using small molecules (FIGS. 8A to 8D),
which supports the assembly of paddlewheel junctions. Annealing of
the sample at 80.degree. C. for 4 h renders a sharper set of peaks,
indicative of the formation of 4-arm polymers with well-defined
cage structures. Because they are far from the MON junction, the
peaks for the EBPA initiator (labeled as g in FIG. 2B) do not
change before and after the assembly.
[0749] The para-bispyridyl L3 functionalized polymer
(PMMA.sub.4k-PBA.sub.19k-L3) showed a completely different NMR
spectrum in the aromatic region when assembled with Pd.sup.2+ (FIG.
2C). The originally sharp peaks for the ligand turn to multiple
broad peaks and shift downfield. For example, the peak at 8.7 ppm
for the a pyridyl proton (labeled as a in FIG. 2C) is split to two
peaks at 9.1 and 9.5 ppm. Prior to annealing, it is known that L3
as a small molecule can form kinetically trapped clusters with many
different sizes and configurations when assembled with
Pd.sup.2+..sup.52, 59 These ill-defined structures significantly
broaden the corresponding NMR peaks. After annealing, the peak at
9.1 ppm merges together with the peak at 9.5 ppm, indicating the
system has reorganized. The fact that the final chemical shifts
agree with ones obtained from the analogous non-polymeric ligand
(FIGS. 9A to 9D) supports the formation of the M.sub.12L.sub.24
cage junctions. Because the M.sub.12L.sub.24 cage is buried in 24
polymer chains, it is difficult to resolve by .sup.1H NMR (broad
peaks) due to slowed relaxation. In contrast, the EBPA initiator
residues located on the periphery of the star polymer are clearly
observed (labeled as g in FIG. 2C).
[0750] Dynamic light scattering (DLS) was used to confirm the
formation of star polymers with each MON core. As shown in FIG. 3A,
particles with a diameter of 12.2.+-.1.9 nm were observed for star
polymers with a paddlewheel core (top image). For polymers with the
M.sub.12L.sub.24 cage junction, the diameter was 22.8.+-.3.9 nm
(bottom image). In both cases, the particles have a narrow size
distribution. The radius of gyration (R.sub.g) of these star
polymers was estimated based on the molecular weight of the
constitutive linear polymers and the number of arms using an ideal
chain model..sup.60 The estimated values (2R.sub.g) for 4-arm and
24-arm star polymers were 12.5 nm and 21.3 nm, respectively, which
agree with the trend of hydrodynamic radius (R.sub.h) measured by
DLS. Thus, though the BCP component is the same in both systems,
and the MONs themselves only differ in size by .about.2 nm, the MON
structure significantly impacts the star polymer size by forcing
the chains into different conformations.
[0751] Atomic force microscopy (AFM) was employed to visualize the
star polymers with the large M.sub.12L.sub.24 cores. FIG. 3B shows
a typical 3D height image of PMMA.sub.4k-PBA.sub.19k-L3 after
annealing with Pd.sup.2+ and spin-coating on the surface of a
silicon wafer. Relatively uniform particles of about 40.+-.8 nm in
diameter were observed (FIG. 3B). The heights of the particles
ranged from 1.5 to 2.8 nm, slightly smaller than what has been
measured for the Fujita spheres (.about.3.5 nm).sup.61, which is
attributed to the fact that when the star polymer dries on the
substrate, the cages collapse due to stretching of the tethered BCP
chains. Polymer stretching and spreading on the surface also
accounts for the discrepancy between the particles sizes measured
using DLS and AFM. To rule out the possibility that the observed
nanoparticles are the result of micelle formation of the BCP
itself, a control experiment was carried with polymers at the same
concentration but in the absence of Pd.sup.2+. In this case, no
particles were found (FIG. 10). These observations were further
verified by transmission electron microscopy (TEM), which revealed
.about.35.+-.6 nm nanoparticles for M.sub.12L.sub.24 star polymers
derived from PMMA.sub.4k-PBA-.sub.19k-L3. Due to their small size,
the four-arm star polymers bearing a paddlewheel MON core (from L2)
were not observable using either AFM or TEM.
BCPMON Formation by BCP Phase Separation
[0752] Having shown that MON assembly can be used to drive the
formation of star polymers in solution with precise sizes and
numbers of BCP arms, BCP phase separation and attractive
interactions between the PMMA blocks were sought to be leveraged to
crosslink these star polymers and provide BCPMONs (FIG. 1A). In the
event, solvent was evaporated and the resulting bulk materials were
thermally annealed to induce microphase separation of the BCPs and
generate glassy PMMA micro domains. Together with the MON
junctions, the PMMA micro domains serve as physical crosslinks to
give elastic BCPMON networks, or BCPMON TPEs (FIG. 1A).
[0753] Small-angle X-ray scattering analysis (SAXS) was used to
study the microphase separation. The SAXS diffractograms of the
linear block copolymer PMMA.sub.4k-PBA.sub.19k (.about.16% PMMA)
without metal and PMMA.sub.4k-PBA.sub.19k-L1 with metal are shown
in FIG. 4A (top left, upper two traces). For both samples, a single
Bragg reflection peak located at q=0.046 .ANG..sup.-1 is observed,
indicating phase-separated structures with a d-spacing, i.e., the
distance between adjacent PMMA-rich domains, equal to 13.7 nm. In
this case, the coordination of Pd by mono-pyridine chain ends has
little effect on the BCP assembly.
[0754] The scattering profiles for the BCPMONs consisting of
identical polymer backbone but different MON cores (e.g.,
PMMA.sub.4k-PBA.sub.19k-L2 and -L3) are shown (FIG. 4A, top left).
Two Bragg peaks are observed for each BCPMON, which suggests that
the incorporation of MONs can facilitate phase separation and long
range ordering of the materials. Similar phenomena have been
observed in other types of star polymer systems..sup.62 The
d-spacing calculated based on the position of the principal peak is
15.0 nm for both -L2 and -L3, an increase of 1.3 nm compared to the
linear polymer due to polymer chain stretching in a star-like
structure when the two blocks phase separate. The q ratio for the
second peak to the primary peak is q2/q1=1: {square root over (3)},
suggesting a sphere or a hexagonally-packed cylinder morphology;
the exact morphology of this BCPMON was not assigned due to limited
number of higher order peaks.
[0755] AFM was used to visualize the phase-separated morphology.
The linear PMMA.sub.4k-PBA.sub.19k does not show appreciable
contrast in the phase profile mainly because the molecular weight
of the polymer is low (FIGS. 11A and 11B). While for
PMMA.sub.4k-PBA.sub.19k-L3 bearing the spherical cages, contrast
between the two blocks is observed (FIG. 4A, top right).
[0756] The mechanical properties of these materials were probed by
oscillatory rheometry. For PMMA.sub.4k-PBA.sub.19k alone, the
storage modulus G' was similar to the loss modulus G''. At lower
angular frequencies, G' was smaller than G'', while at higher
frequencies (.omega.>20 rad/s), G' was slightly greater than
G''; the polymer appears as a very viscous fluid (FIG. 4A, bottom,
bottom trace). In contrast, all of the metal-coordinated materials
derived from PMMA.sub.4k-PBA.sub.19k-L were elastic at all
frequencies; the G' values drastically increased and were
significantly larger than G''. The extent to which G' increased
depended on the geometry of the core. For
PMMA.sub.4k-PBA.sub.19k-L3 bearing the Fujita sphere cores, G' (at
0.1 rad/s, same thereafter) reached as high as 170 kPa, while the
values for PMMA.sub.4k-PBA.sub.19k-L1 and -L2 were 29.4 kPa and
89.3 kPa, respectively. According to the phantom network
theory.sup.60, the difference in shear moduli can be attributed to
the fact that the branch functionality in these BCPMONs is
increasing, from f=4 for -L1 and -L2 to f=24 for -L3. Furthermore,
networks prepared from -L3 may be more uniform as indicated by
SAXS, and thus they may possess fewer elastically ineffective
defects. Although in principle materials bearing ligand L1 and L2
have the same branch functionality, it was found that the material
with L1 is much softer (smaller G'). This observation suggests that
the square-planar junctions in the L1-based material are more
dynamic than the M.sub.2L.sub.4 junctions in the L2-based
BCPMON..sup.63
[0757] The role of the BCP composition, e.g.,
PMMA.sub.8k-PBA.sub.27k and PMMA.sub.8k-PBA.sub.4k, on the BCPMON
properties was also studied. For BCPMONs based on
PMMA.sub.8k-PBA.sub.27k, which has a higher molecular weight and a
slightly larger fraction of PMMA (.about.23% PMMA), a similar trend
is observed where materials with a larger MON junction exhibit
long-range ordering, as evidenced by the sharpening (for
PMMA.sub.8k-PBA.sub.27k-L1) and the presence of higher order
scattering peaks (for PMMA.sub.8k-PBA.sub.27k-L2 and -L3) in SAXS
(FIG. 4B). The d-spacing for PMMA.sub.8k-PBA.sub.27k-L2, and -L3
with MON cores is 19.8 nm, which is 1.0 nm larger than the domain
size of the linear PMMA.sub.8k-PBA.sub.27k 18.8 nm (FIG. 4B, top
left). For PMMA.sub.8k-PBA.sub.27k-L3 with the Fujita sphere MON
core, the scattering pattern follows q1:q2:q3=1: {square root over
(3)}: {square root over (7)}, indicating a hexagonally packed
cylinder phase of PMMA in a PBA matrix. The AFM phase images of the
PMMA.sub.8k-PBA.sub.27k BCP and polyMONs are shown in FIG. 4B (top
right) and FIGS. 12A to 12D. They all show the hexagonal cylinder
phase, agreeing with the SAXS result. Compared to the BCP, which
showed curved cylinders (FIG. 12A), the polyMONs, in particular the
PMMA.sub.8k-PBA.sub.27k-L3, showed ordering in a longer range as
indicated by the relatively straight cylinders observed (FIG. 4B,
top right).
[0758] The mechanical properties of BCPMONs derived from
PMMA.sub.8k-PBA.sub.27k followed similar trends to those based on
PMMA.sub.4k-PBA.sub.19k: the larger the MON core was, the higher
the G' values were (FIG. 4B, bottom). The G' values at 0.1 rad/s
for linear PMMA.sub.8k-PBA.sub.27k, and polyMONs
PMMA.sub.8k-PBA.sub.27k-L1, -L2, and -L3 were 70.7 kPa, 284 kPa,
329 kPa, and 628 kPa, respectively.
[0759] In the case of PMMA.sub.8k-PBA.sub.4k materials, the volume
fraction of the PBA block is increased while the molecular weight
of PMMA is kept as 8k (.about.15% PMMA). In contrast to the samples
discussed above, the SAXS profiles for these materials show
negligible differences between the polymer PMMA.sub.8K-PBA.sub.48k
and materials derived from PMMA.sub.8k-PBA.sub.48k-L1, -L2, or -L3.
The scattering peaks for all the samples could be indexed as q1:
q2: q3=1: {square root over (3)}: {square root over (8)}, implying
a spherical morphology (FIG. 4C, top left). The d-spacing based on
the principle peak is 21.2 nm. AFM phase images, as shown in FIG.
4C (top right) and FIGS. 13A to 13D, reveal the same morphology,
that is, spherical PMMA domains distributed in a PBA matrix.
[0760] For these PMMA.sub.8k-PBA.sub.4k materials, the degree of
polymerization of PBA was increased to .about.385 while the size of
the PMMA block was kept constant. In this case, the PBA block is
large enough to undergo significant chain entanglement (the
entanglement molecular weight of PBA in melt is 29k; DP:
226).sup.64, which leads to a steep increase of G' for the linear
polymer at higher frequency. In the case of the BCPMONs derived
from this polymer, the PBA chain ends are anchored together to MON
cores. This clustering limits chain entanglement, as revealed by
the rheology profile in which the G' values do not increase as
rapidly with frequency. Again, the type of MON involved influences
the mechanical properties of the BCPMON. The G' value for the
BCPMON based on the M.sub.12L.sub.24 MON was greater than that of
paddle wheels and mono-pyridine materials (FIG. 4C, bottom).
[0761] Collectively, the data indicate that the structure of the
MON in each BCPMON dramatically affects the mechanical properties,
and in two of three cases the BCP phase separation, compared to
either free polymer or the square-planar system L1. To rationalize
the role of MON in BCP phase separation, mean field theory was used
with random phase approximation to calculate the spinodal
boundaries of the BCPs taking into consideration the difference in
the assembly architectures including linear and MON containing
polymers..sup.65-66 According to the branch functionality, all
polymers were generalized as (PMMA-PBA).sub.n, where n represents
the number of BCPs attached to the each MON. For instance, in the
case of star polymer with the spherical and the paddle wheel MON
core, n=24 and 4, respectively, while in the case of linear
polymer, n=1. The calculated spinodal curve is shown in FIGS. 5A
and 5B, where .chi. is the Flory-Huggins interaction parameter, N
is the total degree of polymerization of the star polymer, and
f.sub.PMMA is the volume fraction of the PMMA block.
[0762] As shown in FIG. 5A, when n increases from 1 to 4 and then
to 24, the curve boundary shifts upwards and it becomes asymmetric
with the boundary more tilted to the higher f.sub.PMMA side. This
shift means that microphase separation is more likely to occur at a
higher f.sub.PMMA values for the BCPMONs with larger MONs. The
tendency is more clearly presented when the spinodal curves are
normalized by n (FIG. 5B).
[0763] The asymmetric spinodal boundary may arise from two factors.
First, from the molecular architecture: the PBA blocks are anchored
on both ends while the PMMA blocks are only anchored at one end.
Second, since all the PBA blocks are anchored to a junction point,
in this case the MONs, each PBA block tends to be significantly
stretched to relieve the spatial crowding, known as "junction
constraint"..sup.67 Thus, the PBA blocks experience more
conformational restrictions than the PMMA blocks. This effect is
more pronounced when the PBA blocks are short and the number of
constrained polymer chains is large. Therefore, the spinodal
boundary shifts to lower values at the high f.sub.PMMA region
(relatively shorter PBA) with increasing arm numbers.
[0764] According to this model, the star-shaped polymer
architecture may facilitate the self-assembly of the block
copolymers when a) the molecular weight of the arm is small, b) the
fraction of the blocks linked to the star core is high, and c) the
number of arms is large. This model qualitatively agrees with the
experimental results. For BCPMONs based on PMMA.sub.4k-PBA.sub.19k
and PMMA.sub.8k-PBA.sub.48k, which have similar PMMA fractions, the
smaller polymer PMMA.sub.4k-PBA.sub.19k BCPMON showed increased
long range ordering as shown by SAXS, while PMMA.sub.8k-PBA.sub.48k
BCPMON showed no such effect. Because PMMA.sub.8k-PBA.sub.27k has a
larger volume fraction of PMMA than PMMA.sub.8k-PBA.sub.48k, the
BCPMON based on it also showed enhanced phase separation.
[0765] To further expand upon the functionality of BCPMONs, the
formation of BCPMON organogels was investigated through the use of
a selective solvent. Since PMMA has an upper critical solution
temperature (UCST) in 2-ethyl hexanol solvent.sup.57--it dissolves
when heated and aggregates when cooled--the formation of thermally
responsive BCPMON organogels was envisioned. For example, the
mechanical properties of PMMA.sub.8k-PBA.sub.27k-L3 derived BCPMONs
in 2-ethyl hexanol were studied as a function of temperature in
FIG. 6A (upper traces, see key). At low temperatures, G' was
greater than G''; the system was a transparent gel. Upon heating,
G' significantly decreases and becomes smaller than G''; the system
switches to a viscous solution. Depending on the type of MON core
involved, the mechanical properties of the BCPMON gel vary
significantly. When prepared with the same polymer mass fraction,
gels with M.sub.12L.sub.24 MON junctions had a much higher modulus
(G'=6.3 kPa) than ones with M.sub.2L.sub.4 paddle wheel junctions
(G'=0.9 kPa) due to the difference in branch functionality (FIG.
6A). These data are consistent with the trend described above for
BCPMONs in the bulk state. The SAXS profile of the gel shows a
Bragg peak indicative of the aggregated PMMA domains (d-spacing is
25.4 nm). This peak disappears when the gel is heated; the process
is fully reversible (FIG. 6B). Pictures of BCPMONs at 25 and
50.degree. C. are also shown in FIG. 6B, inset.
[0766] The difference in branch functionalities (e.g., 24 vs. 4)
also influenced the spacing between the aggregated PMMA domains in
the BCPMON gels (FIG. 6C), which directly affected the UCST. The
L2-based BCPMON gels had a d-spacing of 27.3 nm while the L3-based
BCPMON gels had a d-spacing of 25.4 nm. Moreover, the sol-gel
transition occurred at different temperatures: 27.degree. C. vs.
37.degree. C. for the paddlewheel- and sphere-containing BCPMON
gels, respectively.
[0767] The stepwise assembly strategy employed herein makes it
possible to incorporate different MON junctions into one BCPMON by
simply mixing the pre-assembled star polymers. Because the type and
geometry of the MON structure may dominate the mechanical
properties and the UCST, it was hypothesized that the materials'
properties could be finely tuned by adjusting the percentage of
different MON junctions in mixed BCPMONs. This idea is demonstrated
by mixing, at different ratios, star polymers with the spherical
MON junctions and the paddlewheel junctions. As can be seen in FIG.
6D ("Modulus" in key), the stiffness of the mixed BCPMON gels
increased almost linearly as the percentage of spherical MON core
increased. The sol-gel transition temperature also changed with the
ratio of different MON junctions (FIG. 6D, "Sol-gel temperature" in
key, FIG. 14). To confirm the presence and integrity of both sphere
cages and paddle wheel cages in the gel, and to rule out thermally
induced exchange of ligands from one MON type with the other, a
model study was carried out with MONs derived from ligands L2 and
L3 without BCPs attached. When mixed at room temperature, .sup.1H
NMR showed separate sets of peaks that corresponded to the
spherical cages and the paddlewheel cages (FIGS. 15A to 15E). After
heating at 50.degree. C., well above the sol-gel transition
temperature, the NMR spectra do not show appreciable changes;
heating at 80.degree. C. is required to induce any changes in the
cage structure.
CONCLUSION
[0768] Herein, Block Co-PolyMONs (BCPMONs), which are a class of
hierarchically structured materials formed via stepwise
metallosupramolecular assembly of MONs followed by BCP microphase
separation, are introduced. It is demonstrated that the choice of
the MON, as determined by small differences in the ligand
structures, may lead to large differences in the microscopic and
mesoscopic structures and mechanical properties of BCPMONs. Due to
the diverse range of MONs and BCPs that could be employed in the
BCPMON paradigm, it is expected that BCPMONs may offer a numerous
opportunities for functional materials design.
REFERENCES
[0769] (1) Leininger, S.; Olenyuk, B.; Stang, P. J., Chem. Rev.
2000, 100, 853-908. [0770] (2) Chakrabarty, R.; Mukherjee, P. S.;
Stang, P. J., Chem. Rev. 2011, 111, 6810-6918. [0771] (3) Cook, T.
R.; Zheng, Y.-R.; Stang, P. J., Chem. Rev. 2013, 113, 734-777.
[0772] (4) Nitschke, J. R., Acc. Chem. Res. 2007, 40, 103-112.
[0773] (5) Smulders, M. M. J.; Riddell, I. A.; Browne, C.;
Nitschke, J. R., Chem. Soc. Rev. 2013, 42, 1728-1754. [0774] (6)
Fujita, M., Chem. Soc. Rev. 1998, 27, 417-425. [0775] (7) Fujita,
M.; Tominaga, M.; Hori, A.; Therrien, B., Acc. Chem. Res. 2005, 38,
369-378. [0776] (8) Oliveri, C. G.; Ulmann, P. A.; Wiester, M. J.;
Mirkin, C. A., Acc. Chem. Res. 2008, 41, 1618-1629. [0777] (9)
Eryazici, I.; Moorefield, C. N.; Newkome, G. R., Chem. Rev. 2008,
108, 1834-1895. [0778] (10) Stang, P. J.; Olenyuk, B., Acc. Chem.
Res. 1997, 30, 502-518. [0779] (11) Ronson, T. K.; Zarra, S.;
Black, S. P.; Nitschke, J. R., Chem. Commun. 2013, 49, 2476-2490.
[0780] (12) Meng, W.; Clegg, J. K.; Thoburn, J. D.; Nitschke, J.
R., J. Am. Chem. Soc. 2011, 133, 13652-13660. [0781] (13) Smulders,
M. M. J.; Jimenez, A.; Nitschke, J. R., Angew. Chem., Int. Ed.
2012, 51, 6681-6685. [0782] (14) Wood, C. S.; Ronson, T. K.;
Belenguer, A. M.; Holstein, J. J.; Nitschke, J. R., Nat. Chem.
2015, 7, 354-358. [0783] (15) McConnell, A. J.; Wood, C. S.;
Neelakandan, P. P.; Nitschke, J. R., Chem. Rev. 2015, 115,
7729-7793. [0784] (16) Fujita, M.; Oguro, D.; Miyazawa, M.; Oka,
H.; Yamaguchi, K.; Ogura, K., Nature 1995, 378, 469-471. [0785]
(17) Sun, W.-Y.; Yoshizawa, M.; Kusukawa, T.; Fujita, M., Curr.
Opin. Chem. Biol. 2002, 6, 757-764. [0786] (18) Harris, K.; Fujita,
D.; Fujita, M., Chem. Commun. 2013, 49, 6703-6712. [0787] (19)
Lehn, J.-M., Chem. Soc. Rev. 2007, 36, 151-160. [0788] (20)
Chambron, J.-C.; Sauvage, J.-P., New J. Chem. 2013, 37, 49-57.
[0789] (21) Brown, A. M.; Ovchinnikov, M. V.; Stern, C. L.; Mirkin,
C. A., J. Am. Chem. Soc. 2004, 126, 14316-14317. [0790] (22)
Newkome, G. R.; Cho, T. J.; Moorefield, C. N.; Baker, G. R.; Cush,
R.; Russo, P. S., Angew. Chem., Int. Ed. 1999, 38, 3717-3721.
[0791] (23) Xie, T.-Z.; Li, J.-Y.; Guo, Z.; Ludlow, J. M.; Lu, X.;
Moorefield, C. N.; Wesdemiotis, C.; Newkome, G. R., Eur. J. Inorg.
Chem. 2016, 2016, 1671-1677. [0792] (24) Xie, T.-Z.; Guo, K.; Guo,
Z.; Gao, W.-Y.; Wojtas, L.; Ning, G.-H.; Huang, M.; Lu, X.; Li,
J.-Y.; Liao, S.-Y.; Chen, Y.-S.; Moorefield, C. N.; Saunders, M.
J.; Cheng, S. Z. D.; Wesdemiotis, C.; Newkome, G. R., Angewandte
Chemie 2015, 127, 9356-9361. [0793] (25) Xie, T.-Z.; Liao, S.-Y.;
Guo, K.; Lu, X.; Dong, X.; Huang, M.; Moorefield, C. N.; Cheng, S.
Z. D.; Liu, X.; Wesdemiotis, C.; Newkome, G. R., J. Am. Chem. Soc.
2014, 136, 8165-8168. [0794] (26) Stadler, A.-M.; Kyritsakas, N.;
Graff, R.; Lehn, J.-M., Chem. Eur. J. 2006, 12, 4503-4522. [0795]
(27) Cook, T. R.; Stang, P. J., Chem. Rev. 2015, 115, 7001-7045.
[0796] (28) Zhou, H.-C.; Long, J. R.; Yaghi, O. M., Chem. Rev.
2012, 112, 673-674. [0797] (29) Furukawa, H.; Cordova, K. E.;
O'Keeffe, M.; Yaghi, O. M., Science 2013, 341, 1230444. [0798] (30)
Furukawa, S.; Reboul, J.; Diring, S.; Sumida, K.; Kitagawa, S.,
Chem. Soc. Rev. 2014, 43, 5700-5734. [0799] (31) Stock, N.; Biswas,
S., Chem. Rev. 2012, 112, 933-969. [0800] (32) Cook, T. R.;
Vajpayee, V.; Lee, M. H.; Stang, P. J.; Chi, K.-W., Acc. Chem. Res.
2013, 46, 2464-2474. [0801] (33) Olenyuk, B.; Whiteford, J. A.;
Fechtenkotter, A.; Stang, P. J., Nature 1999, 398, 796-799. [0802]
(34) Riddell, I. A.; Smulders, M. M. J.; Clegg, J. K.; Nitschke, J.
R., Chem. Commun. 2011, 47, 457-459. [0803] (35) Sun, Q.-F.; Iwasa,
J.; Ogawa, D.; Ishido, Y.; Sato, S.; Ozeki, T.; Sei, Y.; Yamaguchi,
K.; Fujita, M., Science 2010, 328, 1144-1147. [0804] (36) Zhao, C.;
Sun, Q.-F.; Hart-Cooper, W. M.; DiPasquale, A. G.; Toste, F. D.;
Bergman, R. G.; Raymond, K. N., J. Am. Chem. Soc. 2013, 135,
18802-18805. [0805] (37) Pluth, M. D.; Bergman, R. G.; Raymond, K.
N., Acc. Chem. Res. 2009, 42, 1650-1659. [0806] (38) Wang, Z. J.;
Clary, K. N.; Bergman, R. G.; Raymond, K. N.; Toste, F. D., Nat.
Chem. 2013, 5, 100-103. [0807] (39) Fujita, D.; Ueda, Y.; Sato, S.;
Yokoyama, H.; Mizuno, N.; Kumasaka, T.; Fujita, M., Chem 2016, 1,
91-101. [0808] (40) Jansze, S. M.; Cecot, G.; Wise, M. D.; Zhurov,
K. O.; Ronson, T. K.; Castilla, A. M.; Finelli, A.; Pattison, P.;
Solari, E.; Scopelliti, R.; Zelinskii, G. E.; Vologzhanina, A. V.;
Voloshin, Y. Z.; Nitschke, J. R.; Severin, K., J. Am. Chem. Soc.
2016, 138, 2046-2054. [0809] (41) Yan, X.; Li, S.; Pollock, J. B.;
Cook, T. R.; Chen, J.; Zhang, Y.; Ji, X.; Yu, Y.; Huang, F.; Stang,
P. J., Proc. Natl. Acad. Sci. U.S.A 2013, 110, 15585-15590. [0810]
(42) Li, Z.-Y.; Zhang, Y.; Zhang, C.-W.; Chen, L.-J.; Wang, C.;
Tan, H.; Yu, Y.; Li, X.; Yang, [0811] H.-B., J. Am. Chem. Soc.
2014, 136, 8577-8589. [0812] (43) Hardy, J. G.; Cao, X.-y.;
Harrowfield, J.; Lehn, J.-M., New J. Chem. 2012, 36, 668-673.
[0813] (44) Burnworth, M.; Tang, L.; Kumpfer, J. R.; Duncan, A. J.;
Beyer, F. L.; Fiore, G. L.; Rowan, S. J.; Weder, C., Nature 2011,
472, 334-337. [0814] (45) Yan, X.; Cook, T. R.; Pollock, J. B.;
Wei, P.; Zhang, Y.; Yu, Y.; Huang, F.; Stang, P. J., J. Am. Chem.
Soc. 2014, 136, 4460-4463. [0815] (46) Yan, X.; Li, S.; Cook, T.
R.; Ji, X.; Yao, Y.; Pollock, J. B.; Shi, Y.; Yu, G.; Li, J.;
Huang, F.; Stang, P. J., J. Am. Chem. Soc. 2013, 135, 14036-14039.
[0816] (47) Chifotides, H. T.; Dunbar, K. R., Acc. Chem. Res. 2013,
46, 894-906. [0817] (48) Kawamoto, K.; Grindy, S. C.; Liu, J.;
Holten-Andersen, N.; Johnson, J. A., ACS Macro Lett. 2015, 4,
458-461. [0818] (49) Foster, J. A.; Parker, R. M.; Belenguer, A.
M.; Kishi, N.; Sutton, S.; Abell, C.; Nitschke, J. R., J. Am. Chem.
Soc. 2015, 137, 9722-9729. [0819] (50) Zheng, W.; Chen, L.-J.;
Yang, G.; Sun, B.; Wang, X.; Jiang, B.; Yin, G.-Q.; Zhang, L.; Li,
X.; Liu, M.; Chen, G.; Yang, H.-B., J. Am. Chem. Soc. 2016, 138,
4927-4937. [0820] (51) Hosono, N.; Gochomori, M.; Matsuda, R.;
Sato, H.; Kitagawa, S., J. Am. Chem. Soc. 2016, 138, 6525-6531.
[0821] (52) Zhukhovitskiy, A. V.; Zhong, M.; Keeler, E. G.;
Michaelis, V. K.; Sun, J. E. P.; Hore, M. J. A.; Pochan, D. J.;
Griffin, R. G.; Willard, A. P.; Johnson, J. A., Nat. Chem. 2016, 8,
33-41. [0822] (53) BATES, F. S., Science 1991, 251, 898-905. [0823]
(54) Mai, Y.; Eisenberg, A., Chem. Soc. Rev. 2012, 41, 5969-5985.
[0824] (55) Bates, F. S.; Fredrickson, G. H., Phys. Today 1999, 52,
32-38. [0825] (56) Nese, A.; Mosna ek, J.; Juhari, A.; Yoon, J. A.;
Koynov, K.; Kowalewski, T.; Matyjaszewski, K., Macromolecules 2010,
43, 1227-1235. [0826] (57) Seitz, M. E.; Burghardt, W. R.; Faber,
K. T.; Shull, K. R., Macromolecules 2007, 40, 1218-1226. [0827]
(58) Magenau, A. J. D.; Kwak, Y.; Matyjaszewski, K., Macromolecules
2010, 43, 9682-9689. [0828] (59) Yoneya, M.; Tsuzuki, S.;
Yamaguchi, T.; Sato, S.; Fujita, M., ACS Nano 2014, 8, 1290-1296.
[0829] (60) Rubinstein, M.; Colby, R. H., Polymers Physics. Oxford
Univ. Press, 2003. [0830] (61) Kikuchi, T.; Sato, S.; Fujita, D.;
Fujita, M., Chem. Sci. 2014, 5, 3257-3260. [0831] (62) Pakula, T.;
Koynov, K.; Boerner, H.; Huang, J.; Lee, H.-i.; Pietrasik, J.;
Sumerlin, B.; Matyjaszewski, K., Polymer 2011, 52, 2576-2583.
[0832] (63) Sato, S.; Ishido, Y.; Fujita, M., J. Am. Chem. Soc.
2009, 131, 6064-6065. [0833] (64) Yamazaki, H.; Takeda, M.; Kohno,
Y.; Ando, H.; Urayama, K.; Takigawa, T., Macromolecules 2011, 44,
8829-8834. [0834] (65) Shi, W.; Tateishi, Y.; Li, W.; Hawker, C.
J.; Fredrickson, G. H.; Kramer, E. J., ACS Macro Letters 2015, 4,
1287-1292. [0835] (66) Delaney, K. T.; Fredrickson, G. H., Comput.
Phys. Commun. 2013, 184, 2102-2110. [0836] (67) Olvera de la Cruz,
M.; Sanchez, I. C., Macromolecules 1986, 19, 2501-2508.
Materials
[0837] Methyl methacrylate (MMA) and n-butyl acrylate (BA) were
purchased from Sigma-Aldrich and were allowed to pass through a
basic alumina column to remove the inhibitor before use.
Tris(2-(dimethylamino)ethyl)amine (Me.sub.6Tren), Copper(II)
bromide (CuBr.sub.2) and ethyl .alpha.-bromophenylacetate (EBPA)
were purchased from Sigma-Aldrich and were used as received.
3,5-Dibromoanisole, 3-pyridylboronic acid pinacol ester,
4-pyridylboronic acid pinacol ester, and
tetrakis(triphenylphosphine) palladium(0) (Pd(Ph.sub.3).sub.4) were
purchased from Ark Pharm, Inc. and were used as received. All other
reagents and solvents were purchased from Sigma-Aldrich and used
without further purification.
Synthetic Methods
Ligand Synthesis
[0838] Ligands L1 and L3 were synthesized following literature
procedures..sup.1-2 L2 was synthesized using a similar
protocol.sup.1 and is described below.
Synthesis of 3,5-di(pyridin-3-yl)phenol (L2)
[0839] 1,3-dibromo-5-methoxybenzene (2.66 g, 10.0 mmol),
4-Pyridineboronic acid pinacol ester (5.0 g, 24.4 mmol),
tetrakis(triphenylphosphine) palladium(0) (1.16 g, 1 mmol), and
potassium carbonate (13.8 g, 0.1 mol) were added into a 100 ml
single-neck equipped with a magnetic stir bar and capped with a
septum. Under nitrogen atmosphere, 60 ml of DMF along with 2 ml of
H.sub.2O was added and the resulting mixture was stirred for 60 h
at 100.degree. C. After cooling to room temperature, the reaction
residue was diluted with chloroform/methanol (10/1, v/v) and
filtered through CELITE. The filtrate was extracted with brine,
dried over anhydrous Na.sub.2SO.sub.4, and concentrated under
vacuum. Using silica gel column chromatography, the crude product
was purified to yield a light yellow solid. The solid was further
dried under high vacuum, and was dissolved in 100 mL anhydrous
dichloromethane (DCM) in a 250 mL round bottom flask equipped with
a star bar. The solution was cooled to -78.degree. C., and
BBr.sub.3 (50.0 mL, 1.0 M in CH.sub.2Cl.sub.2, 50 mmol) was added
slowly to the flask over the course of 30 min. The reaction was
stirred for another 10 min before it was gradually warmed up to
room temperature and stirred for 8 h. The reaction residue was
poured to 400 mL of iced sodium bicarbonate saturated aqueous
solution to quench. Light yellow precipitation formed and was
collected by filtration. The solid was further purified by washing
with DI water, ethyl ether, and large amount of CH.sub.2Cl.sub.2 to
yield 1.1 g of L2 as white solid (65%). .sup.1H NMR (DMSO-d.sub.6):
.delta. 8.92 (2H, d, J=2.0 Hz), 8.57 (2H, dd, J=4.8 Hz, J=2.0 Hz),
8.10 (2H, dt, J=8.0 Hz, J=2.0 Hz), 7.47 (2H, dd, J=8.0 Hz, J=4.4
Hz), 7.41 (1H, t, J=2.0 Hz), 7.10 (2H, d, J=8.0 Hz). 13C NMR
(DMSO-d.sub.6): .delta. 149.09, 148.25, 139.73, 136.09, 134.76,
124.29, 116.45, 114.16. HRMS (m/z): [M+H].sup.+ calculated for
C.sub.16H.sub.12N20, 249.1022; found, 249.1016.
Synthesis of PMMA
[0840] PMMA polymers were synthesized via atom transfer radical
polymerization (ATRP) following a literature procedure..sup.3
Specifically, to a long-neck Schlenk flask equipped with a magnetic
stir bar were charged with 16.0 mL of MMA, 8.0 mL of 0.095 M EBPA
in anisole, 1 mL of 0.076 M CuBr.sub.2 and 0.149 M
4,4'-Dinonyl-2,2'-bipyridine (dNbpy) in DMF. The system was then
degassed with three freeze-pump-thaw cycles. After the last cycle,
a copper wire (L=3 cm, d=1 mm) cleaned by rinsing with aqueous HCl
was added into the flask under nitrogen. The flask was then stopped
and purged with three vacuum/nitrogen cycles. The system was
allowed to thaw and the flask was heated at 35.degree. C. in an oil
bath. Reaction aliquots were withdrawn at timed intervals to
calculate the conversion based on .sup.1H NMR analysis. The
reaction was quenched at .about.3.5h (35% to 50% conversion) by
opening the flask to air and cooling to room temperature.
Immediately after that, the reaction mixture was diluted in THF and
passed through a column of neutral alumina. The polymer was then
precipitate three times against hexanes, and was collected as white
solids by filtration and dried under vacuum.
Synthesis of PMMA-PBA Block Copolymer
[0841] PMMA-PBA was synthesized via activator regenerated by
electron transfer (ARGET) ATRP. A representative procedure is as
follows. To a long-neck Schlenk flask equipped with a magnetic stir
bar were charged with 1.0 g of PMMA, 10 mL of n-butyl acrylate, 2
mL of 0.047 M Me.sub.6Tren in anisole, and 300 .mu.L of 0.076 M
CuBr.sub.2 in DMF. The resulting solution was degassed by bubbling
nitrogen for 45 min. After that, 1.0 mL of tin(II) 2-ethylhexanoate
in anisole (0.1 M, degassed) was added. The reaction mixture was
then submerged in an oil bath that was maintained at 70.degree. C.
Reaction aliquots were withdrawn at timed intervals to calculate
the conversion based on .sup.1H NMR analysis. The reaction was
quenched at 4 h by opening the flask to air and cooling down to
room temperature. Immediately after that, the reaction mixture was
diluted in THF and passed through a column of neutral alumina to
remove the copper catalyst. The resulting solution was then
concentrated and dried under high vacuum at 50.degree. C.
Block Copolymer Functionalization (Synthesis of PMMA-PBA-L)
[0842] To a long-neck Schlenk flask equipped with a magnetic stir
bar were charged with 1.0 g of PMMA-PBA block copolymer, 200 mg of
Ligand L1, L2, or L3, 300 mg Cs.sub.2CO.sub.3, and catalytic amount
of KI. The Schlenk flask was then evacuated and back-filled with
nitrogen for three cycles. Under nitrogen, 3.0 mL of DMF was added
and the reaction mixture was heated to and maintained at 60.degree.
C. in an oil bath. After 8 h, the DMF was removed under high
vacuum. The functionalized block copolymer was isolated via silica
gel column chromatography (3% methanol in DCM). Due to the polar
pyridine group, the functionalized block copolymers have a higher
polarity, making it possible to purify the polymer using silica gel
chromatography. .sup.1H NMR spectrum of PMMA.sub.4k-PBA.sub.19k-L3
is shown in FIG. 7 as an example.
Characterization Methods
Atomic Force Microscopy (AFM)
[0843] Tapping mode AFM experiments were conducted on an Asylum
Research MFP-3D AFM system (Oxford Instruments). All experiments
were done in air using silicon tips (AC160TS-R3, Asylum Research)
with a spring constant of 26 N/m and a resonance frequency of 300
kHz. For block copolymer microphase-separation imaging, a filtered
polymer solution in toluene (20 mg/mL) was drop-cast onto the
surface of silicon wafer (1 cm.times.1 cm). Before polymer casting,
the wafer was cleaned by rinsing with acetone, hexanes, and
isopropanol and dried under nitrogen. For imaging of the star
polymer containing the MON core, a dilute solution (0.1 mg/mL) of
the star polymer was spin-coated on the surface a cleaned silicon
wafer.
Small Angle X-Ray Scattering (SAXS)
[0844] SAXS experiments were performed at the Sector 12 beamline of
Advanced Photon Source (APS) of Argonne National Laboratory. X-rays
of wavelength 0.89 .ANG. (14 keV) were used. The system was
calibrated using silver behenate as the standard. For the bulk
rubber sample, the exposure time was 0.5 s; for the gel sample, the
exposure time was 1 s. For variable temperature (VT) experiment,
the samples were mounted on a Linkam temperature control stage and
were heated or cooled in situ. 2-dimensional scattering data were
recorded and were converted to 1-dimensional plot via radial
averaging of the 2D pattern. The background scattering (for example
the Kapton tape) was subtracted.
Nuclear Magnetic Resonance Spectroscopy (NMR)
[0845] .sup.1H NMR and .sup.13C NMR were recorded using a Bruker
AVANCE-400 NMR spectrometer. Chemical shifts are reported in parts
per million (ppm), and are referenced to residual solvent peaks.
Scalar coupling constant J was reported in Hertz (Hz).
Gel Permeation Chromatography (GPC)
[0846] GPC analyses were carried out in tetrahydrofuran (THF) at a
flow rate of 1.0 mL/min using an Agilent 1260 Infinity system with
variable-wavelength diode array (254, 450, and 530 nm) and a
refractive index detector. The instrument was calibrated with
low-dispersity poly(styrene) (PS) standards between 1.7 and 3150
kg/mol. The number-averaged molar mass, weight-averaged molar mass,
and dispersity index were abbreviated as M.sub.n, M.sub.w, and D
(D=M.sub.w/M.sub.n).
Rheometry
[0847] Rheology studies of the bulk rubber samples were measured on
an Anto Paar MCR 301 rheometer. A disposable parallel-plate
geometry (radius=12 mm) and a disposable bottom plate were used
together; and the gap between the two plates was about 2 mm.
Frequency sweep experiments were conducted from 0.1 to 100 rad/s at
1% strain, which was in the linear viscoelastic regime as confirmed
using strain sweep experiments. The rubber samples were molded at
120.degree. C. using a TEFLON mode with a radius of 12 mm and a
height of 2 mm. This process also anneals the polymers to induce
phase separation. Rheology experiments of the gel samples were
performed on a TA Discovery HR-2 rheometer. A parallel-plate with a
radius of 20 mm was used and coupled with a bottom plate capable of
varying temperatures using a Peltier heating system. When loading
the sample, a piece of gel (.about.30 mg) was transferred on the
bottom plate and the plate temperature was raised to 50.degree. C.
When the gel turned to a liquid, the top plate was lowered until
the sample was fully sandwiched. The gap between the top and bottom
plates is 0.5 to 1.0 mm. Temperature sweep experiments were
performed where the moduli were measured as a function of
temperature (5 to 70.degree. C.). The strain and the angular
frequency were kept at 1% and 10 rad/s, respectively. The
temperature step was 1.degree. C. per measurement.
Transmission Electron Microscopy (TEM)
[0848] TEM images were obtained using a FEI Tecnai multipurpose
scope (G2 Spirit TWIN). The samples were prepared by spin-coating a
dilute acetonitrile solution (0.1 mg/mL) of the star polymers
containing the MON core on to a carbon coated copper grid. After
drying under vacuum for 10 min, the sample-coated grids were placed
in a small jar saturated with RuO.sub.4 vapor prepared by mixing 30
mg of RuCl.sub.3 and 15 mL of sodium hypochlorite solution (10 to
15%, Sigma). The polymer samples were allowed to stain for 45 min,
and scoped at an electron accelerating voltage of 120 kV.
Dynamic Light Scattering (DLS)
[0849] DLS experiments were performed on a Wyatt Dawn Heleo-II
instrument at 20.degree. C. An acetonitrile solution of the linear
or star polymers is filtered right before each measurement.
Estimation of the Radius of Gyration of the Linear and Star
Polymers4
[0850] The radii of gyration (R.sub.g) was calculated to compare
the size difference between the star-shaped polyMON with different
number of arms.
[0851] The radius of gyration of an ideal linear chain can be
calculated by:
R g 2 = b 2 N 6 ##EQU00001##
where <R.sub.g.sup.2> is the mean-square radius of gyration,
b is the Kuhn length of the polymer, and N is the number of the
Kuhn segments in the polymer chain. For a linear di-block
copolymer, adjustment can be made so that:
R g 2 = b 1 2 N 1 6 + b 2 2 N 2 6 ##EQU00002##
where b.sub.1, N.sub.1, b.sub.2, and N.sub.2, are specific values
for each of the blocks in the copolymer--in this case, PMMA-PBA.
For the simplicity of calculation, =the interaction between PMMA
and PBA was neglected.
[0852] The Kuhn length for PMMA is 1.7 nm and the molecular mass
for a Kuhn segment is 655 g/mol. The Kuhn length for PBA is 1.96
nm, and the molecular mass for the Kuhn segment is 960 g/mol. In
the case of PMMA.sub.4k-PBA.sub.19k,
R g 2 = b 1 2 N 1 6 + b 2 2 N 2 6 = 1.7 2 .times. 4000 / 655 6 +
1.96 2 .times. 19000 / 960 6 = 15.6 nm 2 ##EQU00003##
so that 2R.sub.g=7.9 nm.
[0853] For the star polymers with n arms, the radius of gyration of
an ideal linear chain is:
R g 2 = b 1 2 N 1 total / n 6 .times. ( 3 - 2 n ) + b 2 2 N 2 total
/ n 6 .times. ( 3 - 2 n ) ##EQU00004##
where N.sub.total is the number of Kuhn segments from all arms. For
the 4-arm PMMA.sub.4k-PBA.sub.19k star polymer possessing a
M.sub.2L.sub.4 paddle wheel MON core, n=4, and 2R.sub.g can be
calculated to be 12.5 nm.
[0854] For the 24-arm star polymer possessing a M.sub.12L.sub.24
MON core based on PMMA.sub.4k-PBA.sub.19k, n=24. Considering that
the polymer chains might be stretched due to the junction
constraint.sup.5, it was assumed that polymers are in a good
solvent, instead of a .theta. solvent). In this case,
R g 2 = b 1 2 N 1 total 1.2 / n 6 .times. ( 3 - 2 n ) + b 2 2 N 2
total / n 6 .times. ( 3 - 2 n ) ##EQU00005##
and therefore 2R.sub.g=17.8 nm. Because the MON core is about 3.5
nm in diameter, the size of the star polymer is 21.3 nm.
Calculation of Spinodal Curve
[0855] the thermal unstability limit of the disordered melt of a
star-shape polymer with AB block copolymer--in this case PMMA-PBA
as arms, denoted as (AB).sub.n, where n is the number of arms, was
predicted. For a star-like architecture, all the AB arms are
connected at each B block end. If the A and B blocks have degree of
polymerization (DP) of N.sub.A and N.sub.B, respectively, the total
DP is N=n(N.sub.A+N.sub.B). The average segment length is set to a
for both A and B segments. The structure factor for the (AB).sub.n
star-shaped block copolymer is
S=[S/W-2.chi.].sup.-1
where
S = S AA + S BB + 2 S AB ##EQU00006## W = S AA * S BB - S AB 2
##EQU00006.2## S AA = nS AA ii + n ( n - 1 ) S AA ij ##EQU00006.3##
S BB = nS BB ii + n ( n - 1 ) S BB ij ##EQU00006.4## S AB = nS AB
ii + n ( n - 1 ) S AB ij ##EQU00006.5## S AA ii = n ( N A + nN B )
- 1 g ( N A ) ##EQU00006.6## S AA ij = 1 2 ( nN A + nN B ) - 1 [ g
( 2 N A + 2 N B ) - 2 g ( N A + 2 N B ) + g ( 2 N B ) ]
##EQU00006.7## S BB ii = ( nN A + nN B ) - 1 g ( N B )
##EQU00006.8## S BB ij = 1 2 ( nN A + nN B ) - 1 [ g ( 2 N B ) - 2
g ( N B ) ] ##EQU00006.9## S AB ii = 1 2 ( nN A + nN B ) - 1 [ g (
N A + N B ) - g ( N A ) - g ( N B ) ] ##EQU00006.10## S AB ij = 1 2
( nN A + nN B ) - 1 [ g ( N A + 2 N B ) - g ( N A + N B ) - g ( 2 N
B ) + g ( N B ) ] ##EQU00006.11## g ( f , x ) = 2 y 2 [ fxy + exp (
- fxy ) - 1 ] ##EQU00006.12## y = q 2 a 2 6 ##EQU00006.13##
The structure factor is divergent at the spinodal point, which is
equal to S.sup.-1=0. Based on the structure factor, a spinodal
curve can be drawn to present the thermal unstability limit of the
disordered melt (see main text).
REFERENCES
[0856] (1) Jiang, F.; Wang, N.; Du, Z.; Wang, J.; Lan, Z.; Yang,
R., Chemistry--An Asian Journal 2012, 7, 2230-2234. [0857] (2)
Seredyuk, M.; Gaspar, A. B.; Ksenofontov, V.; Galyametdinov, Y.;
Verdaguer, M.; Villain, F.; Gutlich, P., Inorganic Chemistry 2010,
49, 10022-10031. [0858] (3) Magenau, A. J. D.; Kwak, Y.;
Matyjaszewski, K., Macromolecules 2010, 43, 9682-9689. [0859] (4)
Rubinstein, M.; Colby, R. H., Polymers Physics. Oxford Univ. Press,
2003. [0860] (5) Olvera de la Cruz, M.; Sanchez, I. C.,
Macromolecules 1986, 19, 2501-2508.
Example 2. Preparation and Characterization of BCPMONs of Formula
(C)
[0861] Herein, the synthesis of uniform oligomeric polyMOF ligands
with alkyne end groups via an iterative exponential growth (IEG)
strategy is reported. These ligands were used to prepare a diblock
copolymer via copper-catalyzed azide-alkyne cycloaddition "click"
chemistry with azide-terminated polystyrene (PS). In the presence
of Zn ions, this novel block copolymer forms a BCPMON comprised of
crystalline polyMOF domains embedded in an amorphous PS matrix.
[0862] Block copolymer (BCP) assemblies and metal-organic
frameworks (MOFs) are two classes of self-assembled matter with
vastly different structures and properties. The former may be
derived from covalently linked, flexible polymer chains that may
undergo phase separation on length scales typically ranging from
.about.10-100 nm..sup.1,2 BCPs may be useful for separations,
micropatterning, battery, and electronics technologies..sup.1,2 On
the other hand, MOFs are crystalline networks, optionally with
angstrom-scale order and permanent porosity. These features may
enable functions such as gas and energy storage, catalysis, and
selective separation..sup.3
[0863] There are exciting opportunities to merge the chemistry of
well-defined networks based on metal-ligand coordination (such as
MOFs and metal-organic cages/polyhedra (MOCs)).sup.4-9 and
amorphous materials..sup.10-36 For example, Cohen.sup.23 and
coworkers recently showed that benzene dicarboxylate (BDC) ligands
could be linked together to form oligomers/polymers that could form
"polyMOFs", wherein the ligand struts of MOF-5 were connected by
polymer backbone linkers..sup.23,34 Cohen's polyMOFs were
structurally similar to the parent MOF-5, but they featured greater
ambient stability and recyclability due the polymeric
components.
[0864] The merger of amorphous polymer networks with
multi-component supramolecular assembly to generate soft materials
with novel properties is of interest. For example, "polyMOCs",
which are a class of hybrid materials that feature MOCs embedded in
networks of flexible polymer chains, are reported..sup.26-30 As
part of these efforts, it was recently shown that addition of
Pd.sup.2+ to BCPs with MOC-forming ligands on their chain ends
could induce MOC assembly and subsequent phase separation to yield
polyMOC elastomers where the mechanical properties depend strongly
on the MOC geometry..sup.28
[0865] With an interest in further expanding these types of hybrid
materials, herein we report a novel BCP wherein one block is a
uniform BDC-based oligomer synthesized by iterative exponential
growth (IEG).sup.37-40 and the other is polystyrene (PS) prepared
by atom transfer radical polymerization (ATRP)..sup.41,42 In the
presence of Zn ions, this BCP forms a BCPMON comprised of polyMOF
domains embedded in a PS matrix. This work represents the first
demonstration that a BCP with a suitably designed polyMOF-forming
block can form a composite material with both highly crystalline
polyMOF domains and amorphous polymer domains. BCPMONs could find
applications as robust and easily processable materials for gas
separations.
Preparation of BCPMONs of Formula (C)
[0866] The present study includes the design of a BDC oligomer
suitable for BCP synthesis (FIG. 17). To date, Cohen's BDC-based
polyMOF precursors have been synthesized via step-growth
polymerizations..sup.23,34 Though operationally simple, such
polymerizations suffer from poor control over the degree of
polymerization and broad molar mass distributions. Moreover, they
are not readily amenable to the formation of BCPs. In an effort to
develop a uniform BDC oligomer with defined end functionality, the
IEG approach outlined in FIG. 17 was developed (see Example 2). IEG
is a molecular-doubling strategy that enables the efficient
synthesis of uniform sequence- and stereo-defined
oligomers/polymers with absolute control over molecular
structure..sup.37,38 The approach described in FIG. 17 provides
BDC-based oligomers with precise structures that can subsequently
be modified to tune polyMOF functionality.
[0867] Mono-benzylation of commercially available diethyl
2,5-dihydroxyterephthalate followed by alkylation with
8-bromo-1-octanol provided the IEG "monomer" L.sub.1Et (FIG. 17,
53% yield over two steps..sup.23 In the first IEG cycle (FIG. 17),
L.sub.1Et was subjected to divergent CBr.sub.4/PPh.sub.3
bromination and Pd/C debenzylation reactions followed by convergent
alkylation to provide L.sub.2Et (1.4 g, 80% over three steps).
Repeating this sequence with L.sub.2Et as the starting material
(FIG. 17) provided the uniform tetramer L.sub.4Et (2.3 g, 78% over
three steps). Treatment of L.sub.2Et or L.sub.4Et with KOH at
80.degree. C. provided L.sub.2 (390 mg, 68%) or L.sub.4 (220 mg,
69%), respectively. The structures of these ligands were confirmed
by .sup.1H NMR, .sup.13C NMR, and high-resolution mass spectrometry
(HRMS) (see Example 2). L.sub.2 and L.sub.4 were crystalline, which
attests to their uniformity and contrasts with Cohen's oligomers
(FIG. 23). The octamer L.sub.8Et could be readily synthesized via
another IEG cycle.
[0868] To confirm that L.sub.2 and L.sub.4 could form polyMOFs
analogous to Cohen's, mixtures of each ligand and
Zn(NO.sub.3).sub.2.6H.sub.2O in DMF were heated at 100.degree. C.
for 24 h. Powder X-ray diffraction (PXRD) confirmed the formation
of two new materials, L.sub.2-Zn and L.sub.4-Zn, with reflections
that matched those of Cohen's polyMOFs and the parent MOF-5 (FIGS.
18 A and 18B). Both materials exhibited longer-term stability
towards ambient conditions than MOF-5.23 Similar to Cohen's
polyMOFs, the partial shift observed in the principle PXRD peak
after 1 d and 3 d exposure to ambient conditions for L.sub.2-Zn and
L.sub.4-Zn, respectively, is attributed to the formation of a
non-native polyMOF and not decomposition (the analogous
decomposition of MOF-5 to MOF 69c is not observed via XRD)..sup.23
Notably, the IEG polyMOF crystal structure can be regenerated by
heating the samples in DMF for 1 h at 60.degree. C. (FIG. 18B); the
minor peak broadening observed is similar to Cohen's findings for
regenerated polyMOFs.
[0869] Next, it was sought to install functionality selectively at
one end of the L.sub.2 and L.sub.4, and investigate the impact of
this new functionality on polyMOF formation. A terminal alkyne,
which was planned to be exploited in subsequent copper-catalyzed
azide-alkyne cycloaddition (CuAAC) reactions, was
targeted..sup.43-45 Attempts to directly propargylate the hydroxyl
end of L.sub.2Et or L.sub.4Et led to low yields and mixtures of
products; however, debenzylation followed by selective
propargylation of the resulting phenol (FIG. 19A) provided
L.sub.2Et-alkyne and L.sub.4Et-alkyne in good yields (89% and 86%,
respectively). A new polyMOF ligand L.sub.4Bn was prepared (see
Example 2) via CuAAC coupling of L.sub.4Et-alkyne and benzyl azide
followed by saponification of the BDC sidechains. The PXRD spectrum
of the L.sub.4Bn-derived polyMOF (L.sub.4Bn-Zn) was equivalent to
that of L.sub.4-Zn (FIG. 24), which suggests that the triazole
product of CuAAC coupling does not disrupt polyMOF formation. This
is the first example of a CuAAC-modified polyMOF material; in
principle, L.sub.4Et-alkyne could be used to generate a wide
variety of new polyMOFs depending on the azide used.
[0870] Turning to the target BCPMONs, azide-terminated PS
(PS--N.sub.3 prepared by ATRP and end group substitution, see
Supplementary Information; M.sub.n=3.7 kg mol.sup.-1; =1.08) was
coupled to L.sub.2Et-alkyne and L.sub.4Et-alkyne via CuAAC to yield
L.sub.2EtPS and L.sub.4EtPS, respectively (FIG. 19A). The BCA
groups were revealed by saponification to produce ligands L.sub.2PS
and L.sub.4PS. Matrix-assisted laser desorption ionization
time-of-flight (MALDI-TOF) mass spectrometry (FIG. 19B for
L.sub.4PS) and .sup.1H NMR spectroscopy (FIG. 19C for L.sub.4PS)
confirmed the structures of these BCPs. PXRD spectra for L.sub.2PS
and L.sub.4PS exhibited broad amorphous peaks centered at 190
attributed to PS as well as crystalline features from the BCA
blocks (FIG. 23).
[0871] When L.sub.2PS was exposed to a variety of conditions that
are typically used to generate MOF-5 and related polyMOFs,
crystalline solids were not formed (FIG. 25). Presumably, the very
short ligand block in this copolymer precludes the formation of
crystalline polyMOFs. In future studies, it may be possible to form
polyMOFs with L.sub.2PS and BDC mixtures, where additional BDC
ligands could facilitate the formation of MOF domains and L.sub.2PS
could link these domains to PS domains. When L.sub.4PS was allowed
to react with Zn(NO.sub.3).sub.2.6H.sub.2O a precipitate
(L.sub.4PS--Zn) formed that displayed PXRD reflections similar to
those of polyMOF L.sub.4-Zn and MOF-5, thus confirming the
formation of the target BCPMON (FIG. 20). L.sub.4PS--Zn was
partially soluble in CHCl.sub.3, which is a non-solvent for MOF-5
and L.sub.4-Zn but is a good solvent for PS. L.sub.4PS--Zn appeared
to be stable under ambient conditions for 3 d with no shift in the
PXRD peaks (FIG. 20). After 4 d, a slight shift of the principle
peak to a higher angle was observed. As noted above, Cohen's
polyMOFs displayed a similar shift after 1 d, which is indicative
of the formation of a non-native polyMOF..sup.23 These data also
suggest that the BCPMON is more stable under ambient conditions
than the IEG polyMOF. The hydrophobic PS chains of L.sub.4PS likely
coat the MOF domains within L.sub.4PS--Zn thereby providing
superior stability towards moisture. In addition, L.sub.4PS--Zn
could be regenerated by heating the non-native L.sub.4PS--Zn at
60.degree. C. for 1 h. Again, though the peaks of the regenerated
material were broadened, the peak locations match those of the
pristine material.
Material/General Methods/Instrumentation
[0872] All reagents were purchased from commercial suppliers and
used without further purification unless stated otherwise.
Polystyrene azide was synthesized as previously reported using
ethyl a-bromoisobutyrate initator (O. Altintas, T. Josse, M.
Abbasi, J. De Winter, V. Trouillet, P. Gerbaux, M. Wilhelm and C.
Barner-Kowollik Polym. Chem., 2015, 6, 2854-2868). Column
chromatography was performed on a Biotage.RTM. Isolera One with
Accelerated Chromatographic Isolation flash chromatography system,
using Biotage.RTM. KP-Sil SNAP cartridges at the recommended flow
rates. High-resolution mass spectra (HRMS) were measured on a
Bruker Daltonics APEXIV 4.7 Tesla Fourier Transform Ion Cyclotron
Resonance Mass Spectrometer (FT-ICR-MS) using an electrospray
ionization (ESI) source. X-ray diffraction was performed using a
Rigaku Smartlab Multipurpose Diffracteter with an incident beam Ge
(022) double bounce monochromator and a diffracted beam graphite
monochromator using the variable-slit Bragg Brentano method. No
corrections were made. Samples were cast as powder or from residual
DMF or acetone onto zero background plates. The samples were air
dried for 10 minutes before measurements began. SAXS and WAXS were
preformed using Rigaku H3r Source/Bruker Nanostar SAXS system with
a two-dimensional CCD detector and a beam path length of 60.4 cm.
Samples were prepared in Kapton tape. The Kapton tape scattering
was subtracted. Nuclear magnetic resonance spectroscopy (NMR),
.sup.1H NMR and .sup.13C NMR were recorded using a Bruker
AVANCE-400 NMR spectrometer or a VARIAN Inova-500 NMR spectrometer.
Chemical shifts are reported in parts per million (ppm), and are
referenced to residual solvent peaks. The data were analyzed using
MestReNova or Topspin software. Gel permeation chromatography (GPC)
analyses were carried out in tetrahydrofuran (THF) at a flow rate
of 1.0 mL/min using an Agilent 1260 Infinity system with a
variable-wavelength diode array (254, 450, and 530 nm) and a
refractive index detector for PS--N.sub.3. Matrix-absorption laser
desorption ionization time-of-flight (MALDI-TOF) mass spectra were
recorded with a Bruker model MicroFlex MALDI-TOF at the Koch
Institute for Integrative Cancer Research at MIT. Dithranol in THF
was used as the matrix in negative ion mode. Thermogravimetric
analysis (TGA) was performed using a TA Instruments Discovery TGA.
Samples were run in platinum TGA pans at a ramp rate of 10.degree.
C. per minute from 30 to 600.degree. C. Differential scanning
calorimetry (DSC) was performed on a TA Instruments Discovery DSC,
where each sample was run with a Tzero aluminum pan sealed with a
hermetic lid. Scanning electron microscopy (SEM) was performed in a
Zeiss Merlin high-resolution SEM. Samples were prepared by drop
casting a solution of the desired material on silicon wafers from
dichloromethane suspensions. The samples were allowed to dry
overnight. Transmission electron microscopy (TEM) images were
obtained using a FEI Tecnai multipurpose scope (G2 Spirit TWIN).
The samples were prepared by drop-casting a dilute dichloromethane
suspension (0.1 mg/mL) of the BCPMON onto a carbon coated copper
grid. Consequently, uniform thin films were difficult to obtain.
For positively stained samples, after casting the samples were
dried for 30 minutes, the sample-coated grids were placed in a four
mL vial which was placed in a sealed 20 mL vial containing 1 mL
RuO.sub.4. It was allowed to rest for 30 minutes. The sample was
then removed and allowed to rest for 30 minutes. Gas adsorption
measurements were measured with an ASAP 2020 surface area and pore
size analyzer. .about.50 mg of L.sub.4-Zn was soaked in CHCl.sub.3
for 2 days, decanting and refreshing CHCl.sub.3 every 12 hours.
.about.100 mg of L.sub.4PS--Zn was soaked in CHCl.sub.3 for 12h and
was centrifuged down to isolate .about.20 mg of sample. The samples
were dried on a vacuum line for .about.10 min at room temperature,
and transferred to pre-weighed sample tubes with a filler rods and
degassed at 160.degree. C. for 10 h. The sample tube was reweighed
to obtain a consistent mass for the degassed sample. UHP grade
(99.999%) N.sub.2 were used for all measurements and the sample
temperature was maintained at 77 K.
Preparation of Compound A
##STR00094##
[0874] 10 g (39.3 mmol, 1.0 eq.) of diethyl
2,5-dihydroxyterephthalate, 2.7 g (19.7 mmol, 0.50 eq.)
K.sub.2CO.sub.3, 2.3 mL (19.7 mmol, 0.50 eq.) benzyl bromide and 39
mL acetone were added to a pressure vessel. The vessel was sealed
and the reaction was stirred at 80.degree. C. overnight. The
reaction was cooled and water was added. The solution was
neutralized with 1 M HCl and then extracted with dichloromethane
three times. The extracts were dried with Na.sub.2SO.sub.4,
filtered and concentrated under vacuum. The solid collected was
loaded with minimal DCM and purified by silica gel chromatography
using 0-5% ethyl acetate in hexanes. Unreacted starting material
elutes at 1-2% ethyl acetate in hexanes and can be reisolated. The
product elutes at 2-3% ethyl acetate in hexanes in 61% yield.
.sup.1H (CDCl.sub.3, 400 Hz): 1.32 (2H, t), 1.40 (2H, t), 4.35 (2H,
q), 4.39 (2H, q), 5.07 (2H, s), 7.24-7.54 (7H, m), 10.41 (1H, s).
.sup.13C (CDCl3, 400 Hz): 14.33, 61.60, 62.07, 72.13, 115.00,
115.05, 120.20, 127.45, 128.07, 128.64, 129.45, 149.74, 155.62,
165.53, 169.31. HRMS: calcd. for
C.sub.19H.sub.21O.sub.6[M+H].sup.+, most abundant m/z=345.1333;
found, 345.1338.
Preparation of Compound L.sub.1Et
##STR00095##
[0876] 1.2 g (8.7 mmol, 1.5 eq.) of potassium carbonate, 0.15 g
(0.58 mmol, 0.10 eq.) 18-crown-6, 2.0 g (5.8 mmol, 1.0 eq.) of 1
and 0.95 mL (6.3 mmol, 1.1 eq.) of 8-bromo-1-octanol were dissolved
in a 18 mL of 50:50 DMF/ethanol mixture. The mixture was heated at
80.degree. C. for 16 h in a sealed pressure vessel. The reaction
was then cooled. 70 mL of DI water were added and the reaction was
neutralized with 1 M HCl and then extracted with dichloromethane
three times. The extracts were dried with Na.sub.2SO.sub.4,
filtered and concentrated under vacuum. The oil collected was
loaded with minimal DCM and columned using 0 to 40% ethyl acetate
in hexanes on silica (eluting at 35%) in 86% yield. .sup.1H
(CDCl.sub.3, 400 Hz): 1.24-1.40 (12H, m), 1.40-1.58 (4H, m), 1.77
(2H, dt), 3.58 (2H, t), 3.98 (2H, t), 4.34 (4H, q), 5.09 (2H, s),
7.24-7.49 (7H, m). .sup.13C (CDCl.sub.3, 400 Hz): 14.16, 14.22,
25.63, 25.68, 29.15, 29.21, 29.27, 32.66, 61.26, 61.39, 62.72,
69.67, 71.64, 76.83, 77.15, 77.47, 116.56, 117.38, 124.53, 125.10,
127.19, 127.82, 128.37, 136.57, 151.07, 152.13, 165.85, 165.90.
HRMS: calcd. for C.sub.27H.sub.37O.sub.7[M+H].sup.+, most abundant
m/z=473.2534; found, 473.2549.
Preparation of Compound L.sub.1EtBr
##STR00096##
[0878] A solution of L.sub.1Et 4.3 g (9.0 mmol, 1.0 eq.) and
tetrabromomethane 3.3 g (9.9 mmol, 1.1 eq.) in 39 mL of DCM was
cooled to 0.degree. C. 2.6 g (9.9 mmol, 1.1 eq.) of triphenyl
phosphine was added in four portions every 5-10 minutes. The
reaction was stirred at RT for 1 h. Then an additional 0.25 eq. of
CBr.sub.4 and PPh.sub.3 were added and the reaction was stirred for
an additional 2h. The reaction was concentrated and subjected to
silica gel chromatography (0 to 20% ethyl acetate in hexanes,
eluting at 10%) to provide the product in 89% yield. .sup.1H
(CDCl.sub.3, 400 Hz): 1.30-1.53 (14H, m), 1.75-1.90 (4H, m), 3.40
(2H, t), 4.01 (2H, t), 4.37 (4H, q), 5.12 (2H, s), 7.28-7.40 (4H,
m), 7.43-7.50 (3H, m). .sup.13C (CDCl3, 400 Hz): 14.32, 14.38,
25.95, 28.18, 28.78, 29.22, 29.30, 32.86, 34.02, 61.37, 61.51,
69.81, 71.85, 116.76, 117.59, 124.75, 125.32, 127.35, 127.98,
128.53, 136.74, 151.26, 152.29, 165.93, 166.01. HRMS: calcd. for
C.sub.27H.sub.36BrO.sub.6 [M+H].sup.+, most abundant m/z=535.1690;
found, 535.1684.
Preparation of Compound L.sub.1EtOH
##STR00097##
[0880] A solution of L.sub.1Et 3.8 g (8.0 mmol, 1.0 eq.) and 10%
palladium on carbon 0.85 g (8.0 mmol, 1.0 eq.) in 40 mL ethanol was
sparged with nitrogen for 10 minutes. The solution was then sparged
with hydrogen for 5 minutes and stirred under hydrogen atmosphere
for 18 h at RT. The reaction was filtered to remove the palladium,
concentrated, purified by silica gel chromatography (0 to 50% ethyl
acetate in hexanes, eluting at 30%) and isolated in 99% yield.
.sup.1H (CDCl.sub.3, 400 Hz): 1.27-1.61 (16H, m), 1.79 (2H, tt),
3.60 (2H, t), 3.96 (2H, t), 4.35 (2H, q), 4.41 (2H, q), 7.27 (1H,
s), 7.33 (1H, s), 10.36 (1H, s). .sup.13C (CDCl3, 400 Hz): 14.32,
14.48, 25.95, 28.18, 28.78, 29.22, 29.30, 32.96, 34.02, 61.36,
61.50, 69.81, 71.85, 116.75, 117.58, 124.75, 125.32, 127.34,
127.97, 128.53, 136.74, 151.26, 152.29, 165.93, 166.01. HRMS:
calcd. for C.sub.20H.sub.31O.sub.7 [M+H].sup.+, most abundant
m/z=383.2064; found, 383.2078.
Preparation of Compound L.sub.2Et
##STR00098##
[0882] 0.39 g (2.8 mmol, 1.5 eq.) of potassium carbonate, 0.47 g
(0.18 mmol, 0.10 eq.) 18-crown-6, 0.68 g (1.8 mmol, 0.95 eq.) of
L.sub.1EtOH and 1.0 g (1.9 mmol, 1.0 eq.) of L.sub.1EtBr were
dissolved in a 22 mL of 50:50 DMF/ethanol mixture. The mixture was
heated at 80.degree. C. for 25 h in a sealed pressure vessel. The
reaction was then cooled to RT. 50 mL of DI water were added and
the reaction was neutralized with 1 M HCl and then extracted with
dichloromethane three times. The extracts were dried with
Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The solid
collected was loaded with minimal DCM and was purified by silica
gel chromatography (0 to 60% Ethyl acetate in hexanes, eluting at
30%.). Note: if moisture content is high, a side product will form
that elutes at 60% ethyl acetate. It can be treated with ethanol
and a catalytic amount of HCl under reflux conditions to convert it
back to the desired product. L.sub.2Et isolated in 91% yield.
.sup.1H (CDCl.sub.3, 400 Hz): 1.27-1.61 (30H, m), 1.75-1.85 (6H,
m), 3.63 (2H, t), 4.00 (6H, m), 4.36 (8H, q), 5.12 (2H, s),
7.27-7.51 (9H, m). .sup.13C (CDCl3, 400 Hz): 14.31, 14.37, 25.73,
25.94, 26.03, 29.31, 29.34, 29.36, 29.40, 32.83, 61.38, 61.52,
63.06, 69.83, 69.89, 71.82, 116.67, 116.71, 117.56, 124.70, 124.78,
125.27, 127.34, 127.98, 128.54, 136.72, 151.23, 151.80, 152.29,
165.98, 166.02, 166.19. HRMS: calcd. for C.sub.47H.sub.64NaO.sub.13
[M+Na].sup.+, most abundant m/z 859.4239; found, 859.4255.
Preparation of Compound L.sub.2
##STR00099##
[0884] 670 mg (0.80 mmol, 1.0 eq.) L.sub.2Et and 100 eq. of
potassium hydroxide were dissolved in 29.0 mL of DMF. 15 mL of
water were added and the mixture was heated at 80.degree. C. for 8
hrs. The reaction was acidified with 1 M HCl to a pH of 2. The
product precipitated from solution as a white solid and was
centrifuged at 6000 rpm. The solvent was decanted. The sample was
washed with water three times and dried under vacuum overnight to
give 68% yield. .sup.1H (d6-DMSO, 400 Hz): 1.21-1.47 (23H, m),
1.62-1.72 (6H, m), 3.37 (2H, t), 3.98 (6H, m), 5.15 (2H, s),
7.24-7.41 (7H, m), 7.45-7.50 (2H, m), 12.93 (4H, s). .sup.13C
(d.sub.6-DMSO, 400 Hz): 25.28, 25.30, 25.44, 60.70, 69.15, 70.48,
115.50, 115.57, 115.99, 125.45, 125.63, 127.16, 127.64, 128.30,
137.02, 149.97, 150.43, 150.71, 166.76, 166.82. HRMS: calcd. for
C.sub.39H.sub.48NaO.sub.13 [M+Na].sup.+, most abundant
m/z=747.2987; found, 747.2975. See FIG. 31.
Preparation of Compound L.sub.2EtBr
##STR00100##
[0886] A solution of L.sub.2Et 2.4 g (2.9 mmol, 1.0 eq.) and
tetrabromomethane 1.1 g (3.2 mmol, 1.1 eq) in 24 mL of DCM was
cooled to 0.degree. C. 0.84 g (3.2 mmol, 1.1 eq.) of triphenyl
phosphine was added in four portions every 5-10 minutes. The
reaction was stirred at RT for 1 hr. Then an additional 0.25 eq of
CBr.sub.4 and PPh.sub.3 were added and the reaction was stirred for
an additional 2 h. The reaction was concentrated and the product
was purified by silica gel chromatography (0 to 60% ethyl acetate
in hexanes, eluting at 17%) and isolated in 88% yield. .sup.1H
(CDCl.sub.3, 400 Hz): 1.31-1.55 (28H, m), 1.72-1.92 (8H, m), 3.41
(2H, t), 4.00 (6H, m), 4.37 (8H, q), 5.12 (2H, s), 7.28-7.41 (6H,
m), 7.42-7.51 (3H, m). .sup.13C (CDCl3, 400 Hz): 14.35, 14.41,
25.99, 26.07, 28.22, 28.82, 29.28, 29.36, 29.39, 29.41, 29.44,
32.90, 34.07, 61.40, 61.54, 69.92, 69.97, 71.90, 77.34, 116.73,
116.78, 117.63, 124.78, 124.86, 125.36, 127.39, 128.01, 128.57,
137.68, 151.29, 151.84, 152.35, 166.01, 166.06, 166.19, 166.22.
HRMS: calcd. For C.sub.47H.sub.63BrNaO.sub.12 [M+Na].sup.+, most
abundant m/z=923.3406; found, 923.3416.
Preparation of Compound L.sub.2EtOH
##STR00101##
[0888] A solution of L.sub.2Et 2.1 g (2.5 mmol, 1.0 eq.) and
palladium on carbon 0.27 g (2.5 mmol, 1.0 eq.) in 38 mL of a 50:50
mixture of ethyl acetate:ethanol was sparged with nitrogen for 10
minutes. The solution was then sparged with hydrogen for 5 minutes
and then stirred under hydrogen atmosphere for 18 h at 50.degree.
C. The reaction was filtered to remove the catalyst, concentrated,
and subjected to silica gel chromatography (0 to 60% ethyl acetate
in hexanes, eluting at 40%) to yield the product in 98% yield.
.sup.1H (CDCl.sub.3, 400 Hz): 1.28-1.57 (30H, m), 1.71-1.83 (6H,
m), 3.59 (2H, t), 3.96 (6H, m), 4.29-4.37 (6H, m), 4.40 (2H, q),
7.26 (1H, s), 7.31 (1H, s), 7.32 (1H, s), 10.33 (1H, s). .sup.13C
(CDCl.sub.3, 400 Hz): 14.25, 14.32, 25.70, 25.90, 25.97, 29.28,
29.29, 29.31, 29.35, 32.77, 61.31, 61.33, 61.36, 61.94, 62.94,
69.87, 69.97, 113.78, 114.82, 116.64, 119.78, 124.77, 128.96,
150.14, 151.76, 155.08, 165.61, 166.12, 166.15, 169.30. HRMS:
calcd. for C.sub.40H.sub.58NaO.sub.13 [M+Na].sup.+, most abundant
m/z=769.3770; found, 769.3768.
Preparation of Compound L.sub.4Et
##STR00102##
[0890] 0.35 g (2.5 mmol, 1.5 eq.) of potassium carbonate, 21 mg
(0.08, 0.05 eq.) 18-crown-6, 1.2 g (1.6 mmol, 0.95 eq.) of
L.sub.2EtOH and 1.5 g (1.7 mmol, 1.0 eq.) of L.sub.2EtBr were
dissolved in a 12.5 mL of 50:50 DMF/ethanol mixture. The mixture
was heated at 80.degree. C. for 29 h in a sealed pressure vessel.
The reaction was then cooled. The solvent was removed under vacuum.
The solid was dissolved in a 100 mL of a 50:50 mixture of DCM:DI
water, neutralized with 1 M HCl and then extracted with
dichloromethane three times. The extracts were dried with
Na.sub.2SO.sub.4, filtered and concentrated under vacuum. The solid
collected was dissolved with minimal DCM and purified by silica gel
chromatography (0 to 8% methanol in DCM, eluting at 5%) and
isolated in 90% yield. .sup.1H (CDCl.sub.3, 400 Hz): 1.30-1.58
(58H, m), 1.79 (14H, m), 3.61 (2H, t), 3.98 (14H, t), 4.35 (16H,
q), 5.11 (2H, s), 7.27-7.50 (13H, m). .sup.13C (CDCl.sub.3, 400
Hz): 14.28, 14.34, 25.72, 25.91, 26.00, 29.34, 29.37, 32.80, 61.34,
61.48, 63.00, 69.82, 69.89, 71.81, 116.65, 117.55, 124.70, 124.78,
125.27, 127.32, 127.95, 128.50, 136.70, 151.21, 151.79, 152.26,
165.94, 165.99, 166.15. HRMS: calcd. for C.sub.87H.sub.124NO.sub.25
[M+NH4].sup.+, most abundant m/z=1582.8457; found, 1582.8489.
Preparation of Compound L.sub.4
##STR00103##
[0892] 360 mg (0.23 mmol, 1 eq.) L.sub.4Et and 150 eq. of potassium
hydroxide were dissolved in 8 mL DMF. 3 mL of water were added and
the mixture was heated at 80.degree. C. for 8 hrs. The reaction was
acidified with 1 M HCl to a pH of 2. The product crashed out of
solution as a white solid and was centrifuged at 6000 rpm. The
solvent was decanted. The sample was washed with water three times
and dried under vacuum overnight to give 69% yield. .sup.1H
(d.sub.6-DMSO, 400 Hz): 1.23-1.45 (34H, m), 1.61-1.73 (14H, m),
3.37 (2H, t), 3.93-4.02 (14H, m), 5.15 (2H, s), 7.24-7.34 (8H, m),
7.35-7.41 (3H, m), 7.45-7.49 (2H, m), 12.90 (8H, s). .sup.13C
(d.sub.6-DMSO, 400 Hz): 25.28, 25.44, 28.69, 28.76, 28.92, 32.52,
60.70, 69.15, 70.48, 115.50, 116.03, 125.46, 125.64, 127.16,
127.64, 128.30, 137.02, 149.96, 150.43, 150.72, 166.77, 166.83.
HRMS: calcd. for C.sub.71H.sub.88NaO.sub.25 [M+Na].sup.+, most
abundant m/z=1363.5507; found, 1363.5522. See FIG. 33.
Preparation of Compound L.sub.4EtOH
##STR00104##
[0894] A solution of L.sub.4Et 3.1 g (2.0 mmol, 1.0 eq.) and
palladium on carbon 0.21 g (2.0 mmol, 1.0 eq.) in 240 mL of 50:50
mixture of toluene and ethanol was sparged with nitrogen for 10
minutes. The solution was then sparged with hydrogen for 5 minutes
and then stirred under hydrogen atmosphere for 18 h at 6.degree. C.
The reaction was filtered to remove the catalyst, concentrated, and
subject to silica gel chromatography (0 to 8% methanol in DCM,
eluting at 6%). L.sub.4EtOH was isolated in 96% yield. .sup.1H
(CDCl.sub.3, 400 Hz): 1.32-1.58 (58H, m), 1.74-1.84 (14H, m), 3.63
(2H, t), 3.94-4.04 (14H, m), 4.31-4.39 (14H, m), 4.42 (2H, q), 7.29
(1H, s), 7.33 (6H, s), 7.34 (1H, s), 10.36 (1H, s). .sup.13C
(CDCl.sub.3, 400 Hz): 14.32, 14.38, 25.73, 25.94, 26.03, 29.33,
29.37, 29.42, 32.83. 61.37, 61.42, 61.99, 63.08, 69.90, 70.00,
77.33, 113.78, 114.86, 116.66, 119.86, 124.77, 128.98, 150.28,
151.80, 155.13, 165.63, 166.15, 116.28, 116.20, 269.36. HRMS:
calcd. for C.sub.80H.sub.114NaO.sub.25 [M+Na].sup.+, most abundant
m/z=1497.7541; found, 1497.7594.
Preparation of Compound L.sub.2Et-Alkyne
##STR00105##
[0896] 0.11 g (0.83 mmol, 1.5 eq.) of potassium carbonate, 0.41 g
(0.55 mmol, 1.0 eq.) of L.sub.2EtOH and 0.077 mL (0.72 mmol, 1.3
eq.) of propargyl bromide were dissolved in 5.5 mL of acetone and
2.75 mL ethanol. The mixture was heated at 80.degree. C. for 14 h
in a sealed pressure vessel. The reaction was then cooled. 50 mL of
DI water were added and the reaction was neutralized with 1 M HCl
and then extracted with dichloromethane three times. The extracts
were dried with Na.sub.2SO.sub.4, filtered, and concentrated under
vacuum. The solid collected was dissolved in a minimal amount of
DCM and purified by silica gel chromatography (0 to 80% ethyl
acetate in hexanes, eluting at 25%). The product was obtained in
89% yield. .sup.1H (CDCl.sub.3, 400 Hz): 1.29-1.59 (30H, m),
1.74-1.85 (6H, m), 2.52 (1H, t), 3.62 (2H, t), 3.95-4.03 (6H, mt),
4.31-4.40 (8H, m), 4.72 (2H, d), 7.32 (2H, s), 7.34 (1H, s), 7.52
(1H, s). .sup.13C (CDCl.sub.3, 400 Hz): 14.35, 14.49, 25.74, 25.95,
26.02, 29.34, 29.40, 32.84, 58.60, 61.39, 61.41, 61.59, 63.07,
69.78, 69.91, 76.15, 78.32, 116.36, 116.69, 119.44, 124.71, 124.81,
126.10, 150.13, 151.82, 153.08, 165.55, 165.77, 166.20. HRMS:
calcd. for C.sub.43H.sub.60NaO.sub.13 [M+Na].sup.+, most abundant
m/z=807.3926; found, 807.3906.
Preparation of Compound L.sub.4Et-Alkyne
##STR00106##
[0898] 75 mg (0.54 mmol, 1.5 eq.) of potassium carbonate, 0.53 g
(0.36 mmol, 1.0 eq.) of L.sub.4EtOH and 0.050 mL (0.47 mmol, 1.3
eq.) of propargyl bromide were dissolved in 3.6 mL of acetone and
1.2 mL of ethanol. The mixture was heated at 80.degree. C. for 14 h
in a sealed pressure vessel. The reaction was then cooled. 30 mL of
DI water were added and the reaction was neutralized with 1 M HCl
and then extracted with dichloromethane three times. The extracts
were dried with Na.sub.2SO.sub.4, filtered and concentrated under
vacuum. The solid collected was dissolved in a minimal amount of
DCM and purified by silica gel chromatography (0 to 6% methanol in
DCM, 3%) to provide the product in 86% yield. .sup.1H (CDCl3, 400
Hz): 1.37-1.44 (40H, m), 1.47-1.55 (16H, m), 1.78-1.88 (16H, m),
2.55 (1H, t), 3.67 (2H, dt), 4.03 (14H, t), 3.36-3.44 (16H, m),
4.76 (2H, d), 7.36 (1H, s), 7.39 (1H, s), 7.57 (1H, s). .sup.13C
(CDCl3, 400 Hz): 14.37, 14.40, 25.76, 25.97, 26.06, 29.36, 29.41,
29.45, 29.81, 32.87, 58.62, 61.39, 61.59, 63.11, 69.80, 69.96,
76.15, 116.39, 116.72, 119.47, 124.74, 124.84, 126.12, 150.15,
121.84, 161.56, 165.57, 165.57, 165.78, 166.20. HRMS: calcd. for
C.sub.83H.sub.116NaO.sub.25 [M+Na].sup.+, most abundant
m/z=1535.7698; found, 1535.7708.
Preparation of Compound L.sub.2PS
##STR00107##
[0900] This reaction was set up in a nitrogen atmosphere glovebox.
0.13 g (0.17 mmol, 1 eq.) of L.sub.2Etyne and 0.61 mg of
polystyrene azide (0.16 mmol, 0.95 eq) were dissolved in 5 mL of
THF. 0.005 mL (0.019 mmol, 0.11 eq) of Me.sub.6Tren was added to
2.4 mg (0.017 mmol, 0.1 eq.) of CuBr dissolved in 1 mL of THF
(prepared through iterative dilution) and added to the polystyrene
mixture. The reaction was stirred at RT for 12 hrs and then
concentrated. The mixture was purified by column chromatography
(0-10% Methanol in DCM, eluting at 8%). The concentrated material
was dissolved in 11 mL of DMSO and 100 eq. KOH were added. A few
drops of water were added (the material precipitates if too much
water is added) and was heated at 80.degree. C. for 8 hours. The
reaction was acidified with 1 M HCl to a pH of 2. The product
precipitated from solution as a white solid and was centrifuged at
6000 rpm. The solvent was decanted. The sample was washed,
centrifuged after each wash, with water three times and with
acetone one time, and dried under vacuum overnight. .sup.1H (CDCl3,
500 Hz): 0.82-0.90 (4H, m), 0.91-1.03 (11H, m), 1.18-1.97 (356H, m,
*H.sub.2O present), 2.00-2.11 (b), 3.6-3.70 (2H, t), 4.20-4.33 (6H,
m), 5.24-5.35 (2H, b), 6.24-7.24 (161H, m, *overlap with CDCl3),
7.61 (1H, s), 7.72-7.77 (m, 1H), 7.81-7.87 (3H, s). Note peaks
shift and broaden significantly depending on solvent used and
solvent contamination. Carboxylic acid protons only visible in DMF.
See FIG. 32.
Preparation of Compound L.sub.4PS
##STR00108##
[0902] This reaction was set up in a nitrogen atmosphere glovebox.
0.20 g (0.14 mmol, 1 eq.) of L.sub.4Etyne and 0.49 mg of
polystyrene azide (0.13 mmol, 0.95 eq) were dissolved in 5 mL of
THF. 0.004 mL (0.015 mmol, 0.11 eq) of Me.sub.6Tren was added to
1.9 mg (0.014 mmol, 0.1 eq.) of CuBr dissolved in 1 mL of THF
(prepared via iterative dilution) and added to the polystyrene
mixture. The reaction was stirred at RT for 12 hrs and then
concentrated. The mixture was purified by silica gel chromatography
(0-10% Methanol in DCM, eluting at 8%). The concentrated material
was dissolved in 4.0 mL of DMF and 100 eq. KOH were added. A few
drops of water were added (the material precipitates if too much
water is added) and was heated at 80.degree. C. for 8 hours. The
reaction was acidified with 1 M HCl to a pH of 2. The product
precipitated as a white solid and was centrifuged at 6000 rpm. The
solvent was decanted. The sample was washed, centrifuging after
each wash, with water three times and with acetone one time, and
dried under vacuum overnight. .sup.1H (CDCl.sub.3, 400 Hz):
0.82-0.93 (12H, m), 0.93-1.00 (10H, m), 1.16-1.99 (257H, m,
*H.sub.2O present), 2.00-2.11 (5H, m), 2.11-2.26 (2H, m), 3.62-3.70
(2H, t), 4.20-4.33 (14H, m), 5.23-5.34 (2H, m), 6.27-7.21 (285H, m,
*overlap with CDCl.sub.3), 7.44 (1H, s), 7.71-7.79 (m, 2H),
7.81-7.86 (6H, s). Note peaks shift and broaden significantly
depending on solvent used. Carboxylic acid protons only visible in
DMF. See FIG. 39.
Preparation of Compound L.sub.4Bn
##STR00109##
[0904] L.sub.4Bn was synthesized using the same conditions as those
for L.sub.4PS except benzyl azide was used instead of polystyrene
azide. .sup.1H (d6-DMSO 3, 400 Hz): 1.23-147 (34H, m), 1.63-1.72
(14H, m), 3.37 (2H, t), 3.97 (14H, t), 5.16 (2H, s), 5.61 (2H, s),
7.24-7.40 (12H, m), 7.44 (1H, s), 8.18 (1H, s), 12.89 (8H, s).
.sup.13C (d.sub.6-DMSO, 400 Hz): 25.29, 25.45, 28.70, 28.78, 28.93,
32.53, 52.79, 60.71, 69.16, 115.52, 125.46, 125.53, 127.84, 128.11,
128.76, 150.43, 166.84. HRMS: calcd. for
C.sub.74H.sub.91N.sub.3NaO.sub.25 [M+Na].sup.+, most abundant
m/z=1444.5834; found, 1444.5811.
Characterization of BCPMONs of Formula (C)
[0905] Next, small- and wide-angle X-ray scattering (SAXS and WAXS,
respectively) was used to characterize these materials. For polyMOF
L.sub.4-Zn, the SAXS region was devoid of peaks suggesting a lack
of nanoscale order. In contrast, the WAXS region of L.sub.4-Zn
displayed several sharp peaks indicative of crystallinity. The
SAXS/WAXS curves for BCP L.sub.4PS displayed the opposite pattern:
no sharp peaks were observed in the WAXS region while a broad peak
was observed in the SAXS region that corresponded to a domain
spacing (d) of 9.85 nm. BCP assembly is driven by the Flory-Huggins
interaction parameter, .chi., and the degree of polymerization,
N..sup.2,46,47 Stronger phase segregation occurs when .chi.N is
large. Though x is unknown for L.sub.4PS, N is low; therefore,
.chi.N is likely small, which may explain why the SAXS peak is
broad and relatively weak for this BCP.
[0906] BCPMON L.sub.4PS--Zn displayed broad peaks in the SAXS
region and sharp peaks in the WAXS region (FIG. 21), suggesting
that this material contains a combination of distinct PS and
polyMOF domains as well as polyMOF crystallinity. The SAXS pattern
and domain spacing depended on the sample preparation. When
L.sub.4PS--Zn was annealed at 120.degree. C. for 12 h (above the
T.sub.g of L.sub.4PS as determined by differential scanning
calorimetry, FIG. 26), the SAXS curve displayed a single peak with
a q-value of 0.040 .ANG..sup.-1, which corresponds to a d of 15.7
nm. When L.sub.4PS--Zn was dried under vacuum at RT for 2 d, two
broad peaks were found in the SAXS curve. The principle peak had a
d of 16.1 nm, and the q-ratio of the two peaks was
q.sub.2/q.sub.1=1: 3, which corresponds to either a
hexagonalcylinder or body-centered cubic morphology. The larger d
values for L.sub.4PS--Zn relative to L.sub.4PS reflect a
combination of stretching of the PS chains at the dense
polymer-polyMOF interface and an increase in the size of the
polyMOF regions relative to L.sub.4PS. Though L.sub.4PS has exactly
four MOF-forming ligands per chain, the polyMOF domains can
incorporate several L.sub.4PS molecules. Though there may be a
minimum length of the polyMOF ligand block required for BCPMON
formation (L.sub.2PS did not yield a polyMOF), there is no reason
to suspect that the polyMOF domain size within a BCPMON should be
uniform or directly determined by the length of the polyMOF ligand
block. Thus, the broadness of the SAXS peaks for L.sub.4PS--Zn
likely reflects size dispersity of the polyMOF domains..sup.48,49
In addition, as BCPMON formation is driven by MOF crystallization,
the factors affecting BCP phase segregation (i.e., .chi.N) are not
necessarily relevant; the weak segregation of parent ligand
L.sub.4PS does not indicate that the BCPMON should also have weak
segregation. Nevertheless, the data conclusively validate the
proposed BCPMON design: BCPs with a polyMOF-forming block and an
amorphous polymer block can generate crystalline BCPMONs with both
nano- and angstrom-scale domain spacings.
[0907] These materials were further characterized using scanning
electron microscopy (SEM) and transmission electron microscopy
(TEM). SEM images of polyMOF L.sub.4-Zn revealed oblong, faceted,
and inter-grown crystalline superstructures measuring tens of
microns in size (FIG. 22A). SEM images of BCPMON L.sub.4PS--Zn
revealed a thin polymer film with de-wetted regions due to solvent
evaporation (FIG. 22B); no crystals are observed. These data
suggest that the BCPMON ligand structure limits the growth of
polyMOF crystals to nanoscale dimensions, which is reasonable given
that each ligand possesses a PS chain that must be accommodated
within or on the surface of the polyMOF domain. TEM imaging of
L.sub.4PS--Zn stained with RuO.sub.4 (a positive stain for PS)
revealed a multilayer structure with evidence of nanoscale
ordering. Considering all of the above data, it is proposed that
the BCPMON L.sub.4PS--Zn herein has the structure shown
schematically in FIG. 22D, which features polyMOF domains embedded
within a PS matrix.
[0908] Atomic force microscopy (AFM) was used to study the surface
morphology of L.sub.4PS--Zn. AFM images could not be obtained for
L.sub.4PS--Zn films dried at room temperature due to tip
contamination by the very soft films; however, when the films were
dried at 120.degree. C. for 2 h, AFM phase images revealed the
presence of large and small pores with irregular oval shapes (FIG.
27). The large pores are likely the results of de-wetting, while
the smaller pores, which ranged from 10-25 nm in size, may
correspond to phase-segregated PS and polyMOF domains. Lastly, the
surface areas of these materials were studied using N.sub.2
adsorption methods. The BET and Langmuir surface areas of
L.sub.4-Zn were 476 m.sup.2 g.sup.-1 and 630 m.sup.2 g.sup.-1,
respectively, while the BET and Langmuir surface areas of
L.sub.4PS--Zn were two orders of magnitude lower: 5.68 m.sup.2
g.sup.-1 and 8.48 m.sup.2 g.sup.-1, respectively (FIG. 28). The
observation of the porosity is encouraging, and suggests that these
materials could find utility in gas separations. Furthermore, both
L.sub.4-Zn and L.sub.4PS--Zn could be digested and the ligands
re-used for polyMOF or BCPMON synthesis, respectively, with no loss
in surface area, suggesting potential recyclability of these
materials.
CONCLUSIONS
[0909] Herein, the iterative exponential growth synthesis of
uniform oligomeric ligands for polyMOFs that contain an
end-functionality (an alkyne) for further structural
diversification has been demonstrated. Coupling of a tetrameric
ligand to azide-terminated polystyrene followed by exposure to Zn
ions under traditional conditions for the formation of MOF-5
yielded a BCPMOF. This work represents the first demonstration that
it is possible to generate a crystalline polyMOF-amorphous polymer
hybrid material from a single diblock copolymer. As a result,
BCPMONs represent a new composite material that possesses the
processability of polymers, enhanced stability towards ambient
conditions compared to the parent MOF-5 and polyMOFs, and gas
absorption capacity. The BCPMONs may have other advantageous
properties, such as robust mechanical properties, high surface
areas, and/or tunable, well-defined domain sizes.
REFERENCES
[0910] (1) M. C. Orilall and U. Wiesner, Chem. Soc. Rev., 2011, 40,
520-535. [0911] (2) F. S. Bates, M. A. Hillmyer, T. P. Lodge, C. M.
Bates, K. T. Delaney and G. H. Fredrickson, Science, 2012, 336,
434-440. [0912] (3) R. J. Kuppler, D. J. Timmons, Q. R. Fang, J. R.
Li, T. A. Makal, M. D. Young, D. Q. Yuan, D. Zhao, W. J. Zhuang and
H. C. Zhou, Coord. Chem. Rev., 2009, 253, 3042-3066. [0913] (4) T.
R. Cook, Y. R. Zheng and P. J. Stang, Chem. Rev., 2013, 113,
734-777. [0914] (5) S. Leininger, B. Olenyuk and P. J. Stang, Chem.
Rev., 2000, 100, 853-908. [0915] (6) H. Furukawa, K. E. Cordova, M.
O'Keeffe and O. M. Yaghi, Science, 2013, 341, 1230444. [0916] (7)
H. C. Zhou, J. R. Long and O. M. Yaghi, Chem. Rev., 2012, 112,
673-674. [0917] (8) A. J. McConnell, C. S. Wood, P. P. Neelakandan
and J. R. Nitschke, Chem. Rev., 2015, 115, 7729-7793. [0918] (9)
Q.-F. Sun, J. Iwasa, D. Ogawa, Y. Ishido, S. Sato, T. Ozeki, Y.
Sei, K. Yamaguchi and M. Fujita, Science, 2010, 328, 1144-1147.
[0919] (10) T. Uemura, N. Yanai and S. Kitagawa, Chem. Soc. Rev.,
2009, 38, 1228-1236. [0920] (11) J. Zhang and C.-Y. Su, Coord.
Chem. Rev., 2013, 257, 1373-1408. [0921] (12) H. Li and L. Wu, Soft
Matter, 2014, 10, 9038-9053. [0922] (13) L. L. Yang, X. X. Tan, Z.
Q. Wang and X. Zhang, Chem. Rev., 2015, 115, 7196-7239. [0923] (14)
Y. Y. Zhang, X. Feng, S. Yuan, J. W. Zhou and B. Wang, Inorg. Chem.
Front., 2016, 3, 896-909. [0924] (15) X. W. Liu, T. J. Sun, J. L.
Hu and S. D. Wang, J. Mater. Chem. A, 2016, 4, 3584-3616. [0925]
(16) J. B. Beck and S. J. Rowan, J. Am. Chem. Soc., 2003, 125,
13922-13923. [0926] (17) J. M. Pollino, K. P. Nair, L. P. Stubbs,
J. Adams and M. Weck, Tetrahedron, 2004, 60, 7205-7215. [0927] (18)
J. Reboul, S. Furukawa, N. Horike, M. Tsotsalas, K. Hirai, H.
Uehara, M. Kondo, N. Louvain, O. Sakata and S. Kitagawa, Nat.
Mater., 2012, 11, 717-723. [0928] (19) C. A. Allen, J. A.
Boissonnault, J. Cirera, R. Gulland, F. Paesani and S. M. Cohen,
Chem. Commun., 2013, 49, 3200-3202. [0929] (20) X. Yan, S. Li, J.
B. Pollock, T. R. Cook, J. Chen, Y. Zhang, X. Ji, Y. Yu, F. Huang
and P. J. Stang, Proc. Natl. Acad. Sci. U.S.A, 2013, 110,
15585-15590. [0930] (21) X. Yan, S. Li, T. R. Cook, X. Ji, Y. Yao,
J. B. Pollock, Y. Shi, G. Yu, J. Li, F. Huang and P. J. Stang, J.
Am. Chem. Soc., 2013, 135, 14036-14039. [0931] (22) C. A. Allen and
S. M. Cohen, Inorg. Chem., 2014, 53, 7014-7019. [0932] (23) Z. J.
Zhang, H. T. H. Nguyen, S. A. Miller and S. M. Cohen, Angew. Chem.,
Int. Ed., 2015, 54, 6152-6157. [0933] (24) J. A. Foster, R. M.
Parker, A. M. Belenguer, N. Kishi, S. Sutton, C. Abell and J. R.
Nitschke, J. Am. Chem. Soc., 2015, 137, 9722-9729. [0934] (25) K.
A. McDonald, J. I. Feldblyum, K. Koh, A. G. Wong-Foy and A. J.
Matzger, Chem. Commun., 2015, 51, 11994-11996. [0935] (26) K.
Kawamoto, S. C. Grindy, J. Liu, N. Holten-Andersen and J. A.
Johnson, ACS Macro Lett., 2015, 4, 458-461. [0936] (27) A. V.
Zhukhovitskiy, M. Z. Zhong, E. G. Keeler, V. K. Michaelis, J. E. P.
Sun, M. J. A. Hore, D. J. Pochan, R. G. Griffin, A. P. Willard and
J. A. Johnson, Nat. Chem., 2016, 8, 33-41. [0937] (28) Y. Wang, M.
Zhong, J. V. Park, A. V. Zhukhovitskiy, W. Shi and J. A. Johnson,
J. Am. Chem. Soc., 2016, 138, 10708-10715. [0938] (29) A. V.
Zhukhovitskiy, J. Zhao, M. J. Zhong, E. G. Keeler, E. A. Alt, P.
Teichen, R. G. Griffin, M. J. A. Hore, A. P. Willard and J. A.
Johnson, Macromolecules, 2016, 49, 6896-6902. [0939] (30) Y. Wang,
Y. Gu, E. G. Keeler, J. V. Park, R. G. Griffin and J. A. Johnson,
Angew. Chem., Int. Ed., 2017, 56, 188-192. [0940] (31) N. D. H.
Gamage, K. A. McDonald and A. J. Matzger, Angew. Chem., Int. Ed.,
2016, 55, 12099-12103. [0941] (32) R. Semino, N. A. Ramsahye, A.
Ghoufi and G. Maurin, ACS Appl. Mater. Interfaces, 2016, 8,
809-819. [0942] (33) C. Le Calvez, M. Zouboulaki, C. Petit, L.
Peeva and N. Shirshova, RSC Adv., 2016, 6, 17314-17317. [0943] (34)
Z. J. Zhang, H. T. H. Nguyen, S. A. Miller, A. M. Ploskonka, J. B.
DeCoste and S. M. Cohen, J. Am. Chem. Soc., 2016, 138, 920-925.
[0944] (35) Z.-Y. Li, Y. Zhang, C.-W. Zhang, L.-J. Chen, C. Wang,
H. Tan, Y. Yu, X. Li and H.-B. Yang, J. Am. Chem. Soc., 2014, 136,
8577-8589. [0945] (36) T. Rodenas, I. Luz, G. Prieto, B. Seoane, H.
Miro, A. Corma, F. Kapteijn, F. X. L. I. Xamena and J. Gascon, Nat.
Mater., 2015, 14, 48-55. [0946] (37) S. Binauld, D. Damiron, L. A.
Connal, C. J. Hawker and E. Drockenmuller, Macromol. Rapid Commun.,
2011, 32, 147-168. [0947] (38) J. C. Barnes, D. J. C. Ehrlich, A.
X. Gao, F. A. Leibfarth, Y. Jiang, E. Zhou, T. F. Jamison and J. A.
Johnson, Nat. Chem., 2015, 7, 810-815. [0948] (39) F. A. Leibfarth,
J. A. Johnson and T. F. Jamison, Proc. Natl. Acad. Sci. U.S.A,
2015, 112, 10617-10622. [0949] (40) Y. Jiang, M. R. Golder, H.
V.-T. Nguyen, Y. Wang, M. Zhong, J. C. Barnes, D. J. C. Ehrlich and
J. A. Johnson, J. Am. Chem. Soc., 2016, 138, 9369-9372. [0950] (41)
J. F. Lutz, J. M. Lehn, E. W. Meijer and K. Matyjaszewski, Nat.
Rev. Mater., 2016, 1, 1-14. [0951] (42 K. Matyjaszewski and N. V.
Tsarevsky, Nat. Chem., 2009, 1, 276-288. [0952] (43) O. Altintas,
T. Josse, M. Abbasi, J. De Winter, V. Trouillet, P. Gerbaux, M.
Wilhelm and C. Barner-Kowollik, Polym. Chem., 2015, 6, 2854-2868.
[0953] (44) J. A. Johnson, M. G. Finn, J. T. Koberstein and N. J.
Turro, Macromol. Rapid Commun., 2008, 29, 1052-1072. [0954] (45) J.
A. Johnson, D. R. Lewis, D. D. Diaz, M. G. Finn, J. T. Koberstein
and N. J. Turro, J. Am. Chem. Soc., 2006, 128, 6564-6565. [0955]
(46) F. S. Bates and G. H. Fredrickson, Phys. Today, 1999, 52,
32-38. [0956] (47) F. S. Bates, Science, 1991, 251, 898-905. [0957]
(48) N. A. Lynd and M. A. Hillmyer, Macromolecules, 2005, 38,
8803-8810. [0958] (49) B. van Genabeek, B. F. M. de Waal, M. M. J.
Gosens, L. M. Pitet, A. R. A. Palmans and E. W. Meijer, J. Am.
Chem. Soc., 2016, 138, 4210-4218.
EQUIVALENTS AND SCOPE
[0959] In the claims articles such as "a," "an," and "the" may mean
one or more than one unless indicated to the contrary or otherwise
evident from the context. Claims or descriptions that include "or"
between one or more members of a group are considered satisfied if
one, more than one, or all of the group members are present in,
employed in, or otherwise relevant to a given product or process
unless indicated to the contrary or otherwise evident from the
context. The disclosure includes embodiments in which exactly one
member of the group is present in, employed in, or otherwise
relevant to a given product or process. The disclosure includes
embodiments in which more than one, or all of the group members are
present in, employed in, or otherwise relevant to a given product
or process.
[0960] Furthermore, the disclosure encompasses all variations,
combinations, and permutations in which one or more limitations,
elements, clauses, and descriptive terms from one or more of the
listed claims is introduced into another claim. For example, any
claim that is dependent on another claim can be modified to include
one or more limitations found in any other claim that is dependent
on the same base claim. Where elements are presented as lists,
e.g., in Markush group format, each subgroup of the elements is
also disclosed, and any element(s) can be removed from the group.
It should it be understood that, in general, where the disclosure,
or aspects of the disclosure, is/are referred to as comprising
particular elements and/or features, certain embodiments of the
disclosure or aspects of the disclosure consist, or consist
essentially of, such elements and/or features. For purposes of
simplicity, those embodiments have not been specifically set forth
in haec verba herein. It is also noted that the terms "comprising"
and "containing" are intended to be open and permits the inclusion
of additional elements or steps. Where ranges are given, endpoints
are included. Furthermore, unless otherwise indicated or otherwise
evident from the context and understanding of one of ordinary skill
in the art, values that are expressed as ranges can assume any
specific value or sub-range within the stated ranges in different
embodiments of the disclosure, to the tenth of the unit of the
lower limit of the range, unless the context clearly dictates
otherwise.
[0961] This application refers to various issued patents, published
patent applications, journal articles, and other publications, all
of which are incorporated herein by reference. If there is a
conflict between any of the incorporated references and the instant
specification, the specification shall control. In addition, any
particular embodiment of the present disclosure that falls within
the prior art may be explicitly excluded from any one or more of
the claims. Because such embodiments are deemed to be known to one
of ordinary skill in the art, they may be excluded even if the
exclusion is not set forth explicitly herein. Any particular
embodiment of the disclosure can be excluded from any claim, for
any reason, whether or not related to the existence of prior
art.
[0962] Those skilled in the art will recognize or be able to
ascertain using no more than routine experimentation many
equivalents to the specific embodiments described herein. The scope
of the present embodiments described herein is not intended to be
limited to the above Description, but rather is as set forth in the
appended claims. Those of ordinary skill in the art will appreciate
that various changes and modifications to this description may be
made without departing from the spirit or scope of the present
disclosure, as defined in the following claims.
* * * * *
References