U.S. patent application number 10/283825 was filed with the patent office on 2003-07-17 for methods for pre-determined mass sorting of positional-encoded solid phase synthesis supports.
This patent application is currently assigned to Ontogen Corporation. Invention is credited to Baiga, Thomas J., Cargill, John F., Maiefski, Romaine R..
Application Number | 20030134432 10/283825 |
Document ID | / |
Family ID | 23988631 |
Filed Date | 2003-07-17 |
United States Patent
Application |
20030134432 |
Kind Code |
A1 |
Maiefski, Romaine R. ; et
al. |
July 17, 2003 |
Methods for pre-determined mass sorting of positional-encoded solid
phase synthesis supports
Abstract
A system for producing a library of oligomer comprising at least
two monomers in a positionally determined array comprise a
plurality of synthesis supports, a first plurality of support
carriers wherein each carrier has a uniform array of distinct
support holding positions for the synthesis supports; means for
contacting each array of synthesis supports with a different
monomer to provide a first chemical transformation of the synthesis
supports; a second plurality of support carriers wherein each
carrier has a uniform array of distinct support holding positions
for receiving the chemically transformed synthesis supports
contained in the first plurality of support carriers; transfer
apparatus for transferring a selected row or column of synthesis
supports from each of the first plurality of carriers to each of
the second plurality of carriers to enable the supports in the
second to undergo at least a second chemical transformation; and
whereby each support position in each carrier identifies the
chemical compound thereon.
Inventors: |
Maiefski, Romaine R.;
(Oceanside, CA) ; Cargill, John F.; (Toronto,
CA) ; Baiga, Thomas J.; (Oceanside, CA) |
Correspondence
Address: |
PERKINS COIE LLP
PATENT-SEA
P.O. BOX 1247
SEATTLE
WA
98111-1247
US
|
Assignee: |
Ontogen Corporation
Carlsbad
CA
|
Family ID: |
23988631 |
Appl. No.: |
10/283825 |
Filed: |
October 29, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10283825 |
Oct 29, 2002 |
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09500249 |
Feb 8, 2000 |
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6528324 |
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09500249 |
Feb 8, 2000 |
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08822210 |
Mar 21, 1997 |
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60013897 |
Mar 22, 1996 |
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Current U.S.
Class: |
436/518 ;
435/7.1 |
Current CPC
Class: |
B01J 2219/00497
20130101; G01N 2035/0425 20130101; B01J 2219/00315 20130101; B01J
2219/00659 20130101; C40B 70/00 20130101; G01N 2001/288 20130101;
B01J 2219/00308 20130101; B01J 2219/00592 20130101; B01J 19/0046
20130101; B01J 2219/0072 20130101; C07K 1/047 20130101; G01N
35/1074 20130101; B01J 2219/00585 20130101; B01J 2219/00725
20130101; B01J 2219/00454 20130101; B01J 2219/00691 20130101; B01J
2219/00279 20130101; B01J 2219/00472 20130101; C40B 60/14 20130101;
G01N 35/028 20130101; B01J 2219/00596 20130101; B01J 2219/0059
20130101; B01J 2219/00306 20130101; C40B 50/14 20130101; B01J
2219/00468 20130101; C40B 40/10 20130101; B01J 2219/0054
20130101 |
Class at
Publication: |
436/518 ;
435/7.1 |
International
Class: |
G01N 033/53; G01N
033/543 |
Claims
We claim:
1. A method for producing a library of oligomers of defined
composition, said method comprising: providing a plurality of
synthesis supports equal to the number of oligomers to be
synthesized; providing a first plurality of support carriers,
wherein each support carrier has an array of distinct holding
positions for said synthesis supports, the array defined by at
least three groups of positions; mounting said synthesis supports
in said first plurality of support carriers in said array of
distinct holding positions; contacting each array of synthesis
supports with a different monomer to provide a first chemical
transformation of said synthesis supports in a series of chemical
transformations; providing a second plurality of support carriers
wherein each carrier has an array of distinct holding positions for
receiving said chemically transformed synthesis supports contained
in said first plurality of support carriers, the array defined by
at least three groups of position; redistributing each group of
synthesis supports from each of said first plurality of arrays to
select positions in a separate one of each of said second plurality
of arrays; and repeating the steps of contacting and redistributing
until oligomers containing the desired number of monomers are
obtained, wherein each support position identifies the composition
of the oligomer thereon.
2. A method according to claim 1 wherein said arrays comprise
columns and rows and wherein each group comprises a column or
arrow.
3. A method according to claim 2 wherein each array comprises at
least three columns and three rows.
4. A method according to claim 3 wherein said steps of
redistributing comprises transferring each column of synthesis
supports from each array of each of said first plurality of support
carriers to a column in an array in a separate one of said second
plurality of support carriers.
5. A method according to claim 3 wherein said steps of
redistributing comprises transferring each row of synthesis
supports from each array of each of said first plurality of support
carriers to a row in an array in a separate one of said second
plurality of support carriers.
6. A method according to claim 2 wherein: said steps of
redistributing comprises at least one step of transferring each
column of synthesis supports from each array of each of said first
plurality of support carriers to a column in an array in a separate
one of said second plurality of support carriers; and, at least one
step of transferring each row of synthesis supports from each array
of each of said first plurality of support carriers to a row in an
array in a separate one of said second plurality of support
carriers.
7. A method according to claim 1 wherein: said arrays comprises at
least three columns and rows; and said steps of redistributing
comprises at least one step of transferring each column of
synthesis supports from each array of each of said first plurality
of support carriers to a column in an array in a separate one of
said second plurality of support carriers; and, at least one step
of transferring each row of synthesis supports from each array of
each of said first plurality of support carriers to a row in an
array in a separate one of said second plurality of support
carriers.
8. A method according to claim 2 wherein: all but one of said steps
of redistributing comprises transferring synthesis supports from
selected ones of columns and rows from each array of said first
plurality of support carriers to columns and rows in each array in
said second plurality of support carriers; and said one of said
steps comprises transferring synthesis supports from the other of
columns and rows from each array of said first plurality of support
carriers to columns and rows in each array in said second plurality
of support carriers.
9. A method according to claim 8 wherein the step of contacting
each array of synthesis supports with a different monomer comprises
placing each support carrier in a separate reactor.
10. A method according to claim 1 wherein the step of contacting
each array of synthesis supports with a different monomer comprises
placing each support carrier in a separate reactor.
Description
REFERENCE TO RELATED APPLICATIONS
[0001] This Application is a divisional of U.S. application Ser.
No. 09/500,249, filed Feb. 8, 2000, pending, the contents of which
are hereby incorporated by reference, which is continuation-in-part
of U.S. application Ser. No. 08/822,210, filed Mar. 21, 1997, now
abandoned, which claims the benefit of the filing date of the
Provisional Application No. 60/013,897, filed Mar. 22, 1996.
FIELD OF THE INVENTION
[0002] The present invention relates to apparatus and methods for
carrying out multiple different operations on multiple articles and
establishing the operations on each article by its position in the
array.
[0003] The present invention relates to apparatus and method useful
in creating combinatorial chemistry libraries. More particularly,
the present invention relates to apparatus and methods for
synthesizing spatially-dispersed positionally encoded combinatorial
chemistry libraries of oligomer whereby the synthesis is carried
out on a plurality of solid supports which in turn are distributed
in the form of a series of arrays. The position of each solid
support in each array determines the exact identity of the
oligomer.
BACKGROUND OF THE INVENTION
[0004] The screening of chemical libraries to identify compounds
which have novel pharmacological and material science properties is
a common practice. These chemical libraries may be a collection of
structurally related oligopeptides, oligonucleotides, small or
large molecular weight organic or inorganic molecules. Those
practiced in the art of combinatorial chemistry can accomplish the
synthesis of combinatorial chemical libraries using two general
methods. These methods are known to those skilled in the art as
"spatially-addressable" methods and "split-pool" methods. It is
common to practice these methods using solid support chemical
synthesis techniques as discussed by Gordon, et al.
[0005] A common feature to the spatially-addressable combinatorial
library methods is that a unique combination of monomers is reacted
to form a single oligomer or compound or, alternately, set of
oligomer or compounds at a predefined unique physical location or
address in the synthesis process. An example of the
spatially-addressable method is provided by Geysen et al. and
involves the generation of peptide libraries on an array of
immobilized polymeric pins (a solid support) that fit the
dimensions of a 96-well microtiter plate. A two-dimensional matrix
of combinations is generated in each microtiter plate experiment,
where n.times.m unique oligomer or compounds are produced for a
combination of n+m parallel monomer addition steps. The structure
of each of the individual library members is determined by
analyzing the pin location and the monomers employed at that
address during the sequence of reaction steps in the synthesis.
[0006] An advantage of this method is that individual oligomer or
compound products can be released from the polymeric pin surface in
a spatially-addressable manner to allow isolation and screening of
each discrete member of the library. Another advantage of this
method is that the number of solid supports required is equal to,
i.e. no larger than, the number of library members to be
synthesized. Thus, relatively large quantities, i.e. micromolar
quantities, of individual library members are synthesized in a
practical manner using this method.
[0007] Related to the Geysen pin method are the parallel synthesis
methods which use a reaction vessel system such as that practiced
by Cody, et al. This is the practice of distributing a quantity of
solid supports, such as chemically-derivatized polymeric resin
beads (namely those of the composition polystyrene, polystyrene
grafted with polyethylene glycol, or polyacrylimide, etc.) in a two
dimensional matrix of n.times.m individual reaction vessels
allowing the parallel addition of a set of n.times.m reactive
monomers to produce a set of n.times.m oligomer; or compounds. This
spatially-addressable method has advantages similar to that of
Geysen, et al. Thus, individual oligomer or compound products can
be released from the solid support in a spatially-addressable
manner to allow isolation and screening of each discrete member of
the library. Additionally, the number of solid supports required is
equal to, i.e. no larger than, the number of library members to be
synthesized. Thus, relatively large quantities, i.e. micromolar to
millimolar quantities, of individual library members also are
synthesized in a practical manner using this method.
[0008] Another example of a spatially-addressable method is the
photo lithographic method for synthesizing a collection oligomer or
compounds on the chemically-derivatized surface of a chip (a solid
support) provided by Fodor et al. A variety of masking strategies
can be employed to selectively remove photochemically-labile
protecting groups thus revealing reactive functional groups at
defined spatial locations on the chip. The functional groups are
reacted with a monomer by exposing the chip surface to appropriate
reagents. The sequential masking and reaction steps are recorded,
thus producing a pre-defined record of discrete oligomer or
compounds at known spatial addresses in an experiment. An advantage
of this method is that binary masking strategies can be employed to
produce a unique oligomer or compounds for n masking and monomer
addition cycles. Two important disadvantages of this method are
that a) relatively minute quantities are produced on the surface of
the chip and; b) release and isolation of individual library
members is not technically feasible.
[0009] Split-pool combinatorial library methods differ from
spatially addressable methods in that the physical location of each
unique oligomer or compound is not discrete. Instead, pools of
library members are manipulated throughout the experiment. There
are two major categories of split-pool methods currently in
practice. These are: 1) deconvolution method S7 pioneered by Furka
et al. and Houghten, et al. and 2) encoded methods by Gallop et
al., Still, et al. and others.
[0010] It is common in the practice to employ solid support-based
chemistry for these methods. A collection of solid supports are
split into individual pools. These pools are then exposed to a
series of reactive monomers, followed by a recombination step, in
which the position of all solid supports is randomized. The solid
supports are then split into a new set of individual pools, exposed
to a new series of reactive monomers, followed by a second
recombination step. By repeating this split, react and recombine
process all possible combinations of oligomer or compounds from the
series of monomers employed are obtained, providing a large excess
of solid supports are utilized.
[0011] The number of oligomer or compounds obtained in an
experiment is equal to the product of the monomers employed,
however, the number of chemical transformation steps required is
only equal to the sum of the monomers employed. Therefore, a
geometric amplification of oligomer or compounds is realized
relative to the amount of chemical transformation steps employed.
For instance, only nine (9) transformation steps were employed
using three (3) amino acid monomers in a three step process for the
combinatorial synthesis of 27 peptide oligomer.
[0012] The prior art split-pool methods produce pools of oligomer
or compounds as a product of the experiment. Therefore, the
identification of a specific member of the library is typically
found by screening the pools for a desired activity, biological or
otherwise. The disadvantages of the deconvolution split-pool
methods are that (a) the technique always requires that large
mixtures of oligomer are screened in bioassays, (b) sequential
rounds of resynthesis and bioassay are always required to
deconvolute a library, and (c) since single oligomer are not
produced a library is always stored as a mixture, requiring later
deconvolution.
[0013] In the practice of encoded split-pool methods physical
separation of the solid support is required to accomplish two
tasks: first, to physically isolate the individual library member
after screening and, second, to de-code the identity of the tag and
thus deduce the chemical structure of the member. A disadvantage
specific to the chemically encoded split-pool methods is that
chemical tags introduce potential side reactions and failures both
with orthogonal linkers and with tags, thus requiring compatibility
between the tag chemistry and the chemistry utilized to synthesize
the combinatorial library.
[0014] In practice, both categories of split-pool methods require a
large excess of solid support beads to ensure with reasonable
certainty (99% confidence level) that all possible oligomer are
made when a random split-pool strategy is employed. This is
necessary because the exact identity of each bead (i.e. the
identity of each oligomer) is lost due to the unstructured nature
of the split-pool method. This presents a significant problem when
scaling up these methods for the production of micromole or larger
amounts of individual oligomer in the library.
[0015] The parent application discloses a technique in the
combinatorial chemistry art which can achieve geometric
amplification in the number of library members synthesized relative
to the number of synthetic steps required but, additionally, (a)
avoids the need for chemical encoding steps (b) produces micromolar
or larger amounts of individual oligomer; (c) uses only the number
of solid supports required for the number of possible oligomer in
the library; and (d) produces the oligomer in spatially-dispersed
arrays wherein the identity of the oligomer is determined by its
location in the array.
[0016] There is a need in the combinatorial chemistry art for
apparatus which can carry out the processes and methods of the
parent application.
[0017] There is a need in the combinatorial chemistry art for
apparatus which can carry out the processes and methods of
producing the oligomer in spatially-dispersed arrays wherein the
identity of the oligomer is determined by its location in the
array.
[0018] Glossary
[0019] Monomer: As used herein, a "monomer" is any atom or molecule
capable of forming at least one chemical bond. Thus, a "monomer" is
any member of the set of atoms or molecules that can be joined
together as single units in a multiple of sequential or concerted
chemical or enzymatic reaction steps to form an oligomer. Monomers
may have one or a plurality of functional groups, which functional
groups may be, but need not be, identical. The set of monomers
useful in the present invention includes, but is not restricted to,
alkyl and aryl amines; alkyl and aryl mercaptans; alkyl and aryl
ketones; alkyl and aryl carboxylic acids; alkyl and aryl esters;
alkyl and aryl ethers; alkyl and aryl sulfoxides; alkyl and aryl
sulfones; alkyl and aryl sulfonamides; phenols; alkyl alcohols;
alkyl and aryl alkenes; alkyl and aryl lactams; alkyl and aryl
lactones; alkyl and aryl di- and polyenes; alkyl and aryl alkynes;
alkyl and aryl unsaturated ketones; alkyl and aryl aldehydes;
heteroatomic compounds containing one or more of the atoms of
nitrogen, sulfur, phosphorous, oxygen, and other polyfunctional
molecules containing one or more of the above functional groups;
L-amino acids; D-amino acids; deoxyribonucleosides;
deoxyribonucleotides; ribonucleosides; ribonucleotides; sugars;
benzodiazepines; P-lactams; hydantoins; quinones; hydroquinones;
terpenes; and the like. The monomers of the present invention may
have groups protecting the functional groups within the monomer.
Suitable protecting groups will depend on the functionality and
particular chemistry used to construct the library. Examples of
suitable functional protecting groups will be readily apparent to
skilled artisans, and are described, for example, in Greene and
WUtS,14 which is incorporated herein by reference. As used herein,
"monomer" refers to any member of a basis set for synthesis of an
oligomer.
[0020] For example, the dimers of 20 L-amino acids form a basis set
of 400 "monomers" for synthesis of polypeptides. Different basis
sets of monomers may be used at successive steps in the synthesis
of an oligomer.
[0021] Oligomer: As used herein, an "oligomer" is any chemical
structure that can be synthesized using the combinatorial library
methods and apparatus of this invention, including, for example,
amides, esters, thiGethers, ketones, ethers, sulfoxides,
sulfonamides, sulfones, phosphates, alcohols, aldehydes, alkenes,
alkynes, aromatics, polyaromatics, heterocyclic compounds
containing one or more of the atoms of. nitrogen, sulfur, oxygen,
and phosphorous, and the like; chemical entities having a common
core structure such as, for example, terpenes, steroids, P-lactams,
benzodiazepines, xanthates, indoles, indolones, lactones, lactams,
hydantoins, quiriones, hydroquinones, and the like; chains of
repeating monomer units such as polysaccharides, phospholipids,
polyurethanes, polyesters, polycarbonates, poly ureas, polyamides,
polyethyleneimines, poly arylene sulfides, polyimides,
polyacetates, polypeptides, polynucleotides, and the like; or other
oligomer as will be readily apparent to one skilled in the art upon
review of this disclosure. Thus, an "oligomer" of the present
invention may be linear, branched, cyclic, or assume various other
forms as will be apparent to those skilled in the art. Thus,
"oligomer" may be used synonymously or interchangeably with
"compound", thus describing any structure, organic or inorganic,
which can be produced in a sequential fashion via the addition of
monomeric units as described above.
[0022] Solid Support: A "solid support" as used herein is a
material, or combination of materials, having a rigid or semi-rigid
surface and having functional groups or linkers, or that is capable
of being chemically derivatized with functional groups or linkers,
that are suitable for carrying out chemical synthesis reactions.
Such materials will preferably take the form of small beads,
pellets, disks, cylinders, capillaries, hollow fibers, needles,
solid fibers, cellulose beads, pore-glass beads, silica gels,
polystyrene beads cross-linked with divinylbenzene and optionally
grafted with polyethylene glycol, grafted co-poly beads,
poly-acrylamide beads, latex beads, dimethylacrylamide beads
optionally cross-linked with N,N'-bis-hycryloyl ethylene diamine,
polydimethylacrylamide beads crosslinked with polystyrene, glass
particles coated with a hydrophobic polymer, or other convenient
forms. "Solid supports" may be constructed such that they are
capable of being transferred mechanically from one support carrier
to another support carrier.
[0023] Linker: A "linker" is a moiety, molecule, or group of
molecules attached to a solid support and spacing a synthesized
oligomer from the solid support. Typically a linker will be
bifunctional, wherein said linker has a functional group at one end
capable of attaching to a monomer, oligomer, or solid support, a
series of spacer residues, and a functional group at another end
capable of attaching to a monomer, oligomer, or solid support. The
functional groups may be, but need not be, identical. Additionally,
said linker may be cleaved by a chemical transformation such that
the synthesized oligomer, or part of the synthesized oligomer, or
the synthesized oligomer and the linker, or the synthesized
oligomer and part of the linker may be chemically separated from
the solid support, linker, or both.
[0024] Carrier: A carrier as used herein is a portable support
structure or platform which may be in the form of a tray, grid or
other form for positionally holding s plurality of solid supports
in predetermined spatial arrays. A carrier can take any number of
forms suitable for receiving and temporarily holding solid supports
in a desirable spatial array A "donor carrier" is a carrier that is
loaded with solid supports and is in a position to transfer the
solid supports to a donee carrier. A "donee or recipient carrier"
is an empty carrier that is readied or positioned to receive solid
supports from a donor carrier.
[0025] Column: The term "column" as used herein for the arrangement
of the solid supports means a vertical row. That is, column means a
row that extends toward and away from the observer or vertically
from top toward the bottom of a page.
[0026] Row: The term row as used herein for the arrangement of the
solid supports means a horizontal row that extends left to right on
a page.
SUMMARY AND OBJECTS OF THE INVENTION
[0027] A primary object of the present invention is to provide an
apparatus and method for the synthesis of a spatially-dispersed
combinatorial library of oligomer, in which the oligomer are
distributed in a controlled manner.
[0028] In accordance with a primary aspect of the invention, a
system for moving multiple supports in parallel through multiple
different synthesis steps to provide a library of oligomer
comprises at least two monomers, a plurality of synthesis supports,
a first plurality of support carriers wherein each carrier has a
uniform array of distinct support holding positions for said
synthesis supports, means for contacting each array of synthesis
supports with a different monomer to provide a first chemical
transformation of said synthesis supports, a second plurality of
support carriers wherein each carrier has a uniform array of
distinct support holding positions for receiving said chemically
transformed synthesis supports contained in said first plurality of
support carriers, transfer apparatus for transferring a selected
row or column of synthesis supports from each of said first
plurality of carriers to each of said second plurality of carriers
to enable the supports in the second to undergo at least a second
chemical transformation, and whereby each support position in each
carrier identifies the chemical compound thereon.
[0029] An object of the present invention is to provide an improved
apparatus and method for the synthesis of a spatially-dispersed
combinatorial library of oligomer, in which the oligomer are
distributed in a controlled manner. These oligomers are comprised
of a series of monomers which are introduced into the oligomer in a
sequential and stepwise fashion via chemical transformation steps
(hereafter referred to as "steps"). These monomers are comprised of
subsets of monomers such that the first subset of monomers is
introduced in the first step, the second set of monomers is
introduced in the second step, etc. The method further comprises
apparatus for holding a plurality of solid supports in a sequence
of spatial arrays during steps of chemical transformation steps and
moving them in a sequential and stepwise fashion between
transformation steps. The method comprises means for introducing
the monomers in a sequential and stepwise fashion on a series of
solid supports. The number of supports equals the number of
oligomer in the library.
[0030] A novel aspect of this apparatus and process as
distinguished from the prior art is that the supports are arranged
in, and subsequently redistributed in a controlled manner between,
a series of arrays. This series of arrays are enabled by means for
holding the supports in physically discrete locations such that the
exact identity of each support is provided by its location. The
series of arrays of supports are placed in a further series of
reaction vessels for the individual steps of an oligomer synthesis.
After each step in the oligomer synthesis the supports are
redistributed in a predetermined controlled manner from one series
of arrays to a next series of arrays.
[0031] A further novel aspect of this process is that between each
step the redistribution of the supports is carried out in a
controlled fashion, such that all possible combinations of possible
oligomer are synthesized. A further novel aspect of this process is
that the positions of all supports are known during the synthesis
experiment such that the identity of an oligomer is unequivocally
established by its physical location. Thus, the applied method
achieves a geometric amplification in the number of library members
synthesized relative to the number of synthetic steps required
while providing individual library members in a spatially dispersed
format. Thus, the use of a tagging system is eliminated for a
split-pool synthesis experiment.
[0032] The apparatus and method has utility in the production of
oligomer which are available for screening in assays for novel
biological, chemical, or physical properties which may have
commercial value. Further, the structures of these oligomer are
readily identifiable by virtue of their physical location. The
apparatus further provides a means for producing each oligomer in a
discrete physical location which allows any pre-determined oligomer
to be readily isolated from all other oligomer in the library. Yet
another advantage of the invention is that no excess of solid
supports is required, thus enabling a larger scale of
synthesis.
BRIEF DESCRIPTION OF THE DRAWINGS
[0033] The above and other objects and advantages of the present
invention will be appreciated from the following specification when
read in conjunction with the accompanying drawings wherein:
[0034] FIGS. 1A & B is a schematic illustration of a flow
diagram for a three by three array through a three step chemical
transformation;
[0035] FIG. 2 is a top plan view of a system in accordance with an
exemplary embodiment of the invention;
[0036] FIG. 3 is a perspective view of the system of FIG. 2;
[0037] FIG. 4 is a perspective view of the support to carrier
loading apparatus of the system of FIG. 2;
[0038] FIG. 5 is a side elevation view of the apparatus of FIG.
4;
[0039] FIG. 6 is an exploded view of a reaction chamber of the
system of FIG. 2;
[0040] FIG. 7 is a side elevation view in section of the reaction
chamber taken on line 7-7 of FIG. 2;
[0041] FIG. 8A is a perspective view of the support carrier to
carrier transfer apparatus of the system of FIG. 2 showing the
support transfer device in one orientation;
[0042] FIG. 8B is a view like FIG. 8A showing the support transfer
device in another orientation;
[0043] FIG. 8C is a perspective view from below of the carrier to
carrier transfer head of the apparatus of FIG. 8A;
[0044] FIG. 8D is a perspective view of the carrier to carrier
transfer head of the apparatus of FIG. 8A;
[0045] FIG. 9A is a perspective view of the carrier to carrier
transfer apparatus of FIG. 8A and the transport carousel;
[0046] FIG. 9B is an enlarged partial view of the transfer head of
the carrier to carrier transfer apparatus of FIG. 9A;
[0047] FIG. 10 is a perspective view of an exemplary embodiment of
a solid support for use in the system of FIG. 2;
[0048] FIG. 11A is an exemplary embodiment of a carrier for a
plurality of solid supports for use in the system of FIG. 2;
[0049] FIG. 11B is side elevation sectional view taken on line
11B-11B of FIG. 11A;
[0050] FIG. 12A B & C are enlarged side elevation sectional
views of the carrier to carrier transfer head of the apparatus of
FIG. 8A carrying out the process of transfer; and
[0051] FIG. 13 a schematic illustration of a control diagram for
the system of FIG. 2; and
[0052] FIG. 14 is a perspective view of an exemplary embodiment of
a 24.times.24 solid support array using four 12.times.12 solid
support carriers for use in the system of FIG. 2
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0053] The system and method described herein is suitable for the
synthesis of a library of oligomers comprised of two, three, or
more sets of oligomer. However, the system described is most
suitable for the synthesis of a library of oligomers comprised of
three monomer subsets. The sums of monomers in each of these
subsets may be variable. However, conveyance of the methodology to
those practiced in the art may be initially illustrated when the
sum of all monomers in each subset is equal. The sum of monomers in
each subset is defined by n in which n is a positive integer. The
solid supports are preferably arranged in a series of arrays of
dimension n.times.n on suitable carriers. There are a total of n
such arrays required for the synthesis of such a library.
Therefore, the total number of oligomer in a three step synthesis
is the product n.times.n.times.n.
[0054] The n arrays of solid supports are preferably arranged in
support carriers (hereafter referred to as "carriers"). Each
carrier holds an n.times.n array of solid supports. Alternatively,
several carriers may be used to hold an n.times.n array of
supports. However, preferably the carriers are of sufficient size
to hold an entire n.times.n array of supports. Thus, preferably
there are n carriers which are placed in n reaction vessels for
each chemical transformation step such that each individual monomer
from a subset of n monomers is reacted with the supports in each
individual reaction vessel.
[0055] A further novel aspect of this system and process as
distinguished from the prior art is the system and method by which
the supports are redistributed from one series of arrays to the
next series of arrays between chemical transformation steps. This
novel method is illustrated in FIG. 1 for a three-step
combinatorial synthesis using three subsets of monomers, each
subset containing three monomers (i.e. n=3), to produce a library
of 27 (i.e. n.times.n.times.n=27) oligomer. The supports are
arranged as arrays of rows and columns on the carriers and reacted
with a first subset of monomers.
[0056] After chemical transformation step #1, the columns of
supports in the first series of arrays are redistributed such that
the first column from the first array in the first series is
transferred to the first column of the first array in the second
series; the second column from first array in the first series is
transferred to the first column of the second array in the second
series; the third column from the first array in the first series
is transferred to the first column of the third array in the second
series. The first, second and third columns of supports from the
second and third arrays in the first series are redistributed to
the second series of arrays for chemical transformation step #2 in
a similar fashion.
[0057] After having completed this redistribution process, the
arrays of supports undergo chemical transformation step #2. After
step #2 the arrays are redistributed again to a new series of
arrays. The method of redistribution is similar to that used after
the chemical transformation step #1, however, it is the individual
rows of each array that are redistributed rather than the columns
described above. The redistribution as described above is shown in
FIG. 1. Thus, the rows of supports in the second series of arrays
are redistributed such that the first row from the first array in
the second series is transferred to the first row of the first
array in the third series; the second row from first array in the
second series is transferred to the first row of the second array
in the third series; the third row from the first array in the
second series is transferred to the first row of the third array in
the third series. The first, second and third rows of supports from
the second and third arrays in the second series are redistributed
to the third series of arrays for chemical transformation step #3
in a similar fashion.
[0058] It should be noted that the redistribution of supports
between the chemical transformation steps #1 and #2 and between
steps #2 and #3 is functionally identical if one simply reorients
the arrays such that rows become columns and columns become rows
(such as accomplished by a 90 degree rotation). If such a
reorientation of the second series of arrays occurs then the
columns from the second series of arrays are redistributed to
columns in the third series of arrays. Following this second
redistribution, chemical transformation step #3 is carried out on
the supports. Using this redistribution method, all 27 possible
combinations of monomers are ensured thus producing a combinatorial
library of 27 oligomer.
[0059] It may be appropriate to indelibly mark the carriers which
hold the arrays using a means to ensure that rows are recognized as
distinct from columns in each array. Additionally, each carrier may
also be indelibly marked to distinguish the contents of its arrays
uniquely from other carriers arrays. Preferably, a barcode reading
device may be used to query this information from a barcode placed
across the top of the columns or beside the rows of each
carrier.
[0060] As appreciated by those familiar in the art, this
redistribution method for an n.times.n.times.n library is
efficient, transferring entire columns or entire rows of supports
simultaneously. The synthesis of these 27 oligomer was accomplished
with three chemical transformation steps involving a total of only
3 individual reaction vessels for each step. The products from the
library synthesis experiment are held in discrete locations, thus
allowing for the identification and isolation of each individual
library member. Additionally, this redistribution method is
amenable to automation via robotics.
[0061] The above illustration describes a method for synthesizing a
library of oligomer of very modest size. The technique is readily
extrapolated to the synthesis of much larger libraries, e.g. one
million oligomer using a three step synthesis with arrays of
dimension 100.times.100 supports, 100 carriers, 100 monomers in
each step. Thus a total of 100 reaction vessels can be employed to
produce a library of one million members, all spatially-dispersed,
individually identifiable and individually isolated. Those
practiced in the art will appreciate that spatially-dispersed
techniques as previously practiced by Geysen, Cody, and Ellman's
would have required 3 million reaction vessels to produce an
identical resulting oligomer library.
[0062] In order to further illustrate the practice of the present
invention, a system and apparatus are illustrated for carrying the
methods and process of the invention. While these examples
illustrate methods for three combinatorial steps, the methods may
be extended to synthesize combinatorial libraries which require
more than three combinatorial steps as will become obvious to those
persons skilled in the art. In addition, the methods may be carried
out using unsymmetrical arrays as will be apparent to those of
skill in the art.
[0063] An exemplary embodiment of a suitable system carrying out
the steps and methods of the aforementioned process for practice of
the present invention is schematically illustrated in FIGS. 2 and 3
and designated generally by the numeral 10. The process can be
carried out in any number of different ways with the steps carried
out partially or entirely automatically by machine and/or partially
or entirely manually. The illustrated system comprises three main
subsystems. These comprise a solid support loading system or unit
100, a reaction chamber system or unit 200 and a redistribution
system or unit 300. The solid support loading system, designated
generally at 100, comprises a solid support source, a support
carrier or carrier source and means for loading the solid supports
into the support carriers. The reaction chamber system, designated
generally 200, comprises an array of reaction chambers to receive
the supports for a series of chemical transformations. The transfer
and redistribution unit, designated generally 300, comprises a
transfer unit for each reaction chamber which works in conjunction
with a conveyer system to transfer and redistribute the solid
supports in a predetermined controlled fashion from carriers to
subsequent carriers for subsequent chemical transformations. The
multiple supports move in a predetermined controlled fashion in
parallel from carrier to carrier through multiple different
synthesis steps to provide a library of oligomer comprising at
least two monomers wherein the oligomer are identifiable by their
location or position in the carriers of the system. This
predetermined systematic transfer or redistribution of the supports
from carrier to carrier through the many steps of the process
ensures that any oligomer can be identified by the location of its
support at any time in the system.
[0064] The solid support loading system, as best illustrated in
FIGS. 4 and 5, comprises a hopper 102 for containing source or
supply of solid supports on which chemical transformation is to be
carried out for loading into support carriers. The hopper 102 has
upstanding sloped sides sloping downward and converging to a bottom
central opening 104 which may preferably have a grid like pattern
of openings matching the openings in a shuttle carrier. A generally
box like upstanding chute 106 is adapted to hold a supply of a
plurality of carriers 108 for receiving and mounting the solid
supports. A track comprising a pair of spaced apart rails 110
connect the chute 106 to a central transfer position beneath a
transfer punch mechanism designated generally at 112 where solid
supports are loaded from a shuttle onto or into the supports. An
upper track comprising a pair of rails 114 guide a transfer shuttle
116 from the hopper 102, where it is loaded with solid supports, to
the central transfer position where the solid supports are
transferred to the carriers. The shuttle moves to a position above
a carrier where the punch transfers the supports from the shuttle
to the carrier. Loaded carriers are transferred along a track
comprising a pair of spaced rails 118 to a reaction chamber or to a
position to be retrieved for transfer to a reaction chamber. The
carriers 108 are moved by suitable means such as a pneumatic ram
130 to the transfer position beneath transfer punch 112. An
actuator such as a pneumatic cylinder 132 moves the shuttle 116
back and forth between a support loading position beneath hopper
102 and a transfer position beneath the transfer punch 112. Loaded
carriers may be pushed out along track 118 from beneath the
transfer punch by suitable transport means such as a pneumatic ram
134.
[0065] The solid support transfer mechanism comprises a housing or
head 120 in which is mounted a vertically reciprocating plunger
having a plurality of vertically oriented punch pins 122. The
reciprocating plunger in head 120 is operated by a suitable power
unit such as a linear motor which is preferably a pneumatic
cylinder 124 via a line 126 to a suitable pressurized air source.
It may also be operated by an electrical solenoid or other suitable
linear motor. The power unit 124 operates to move the plunger
vertically downward to transfer the solid supports from the shuttle
to the receiving carrier. The plunger has a plurality of pins in
lines corresponding to the holding positions of the solid supports
in the shuttle and carriers.
[0066] The system includes a plurality of reaction chambers 200
sufficient in number to carry out the desired reactions and produce
the required number of oligomer. In a preferred system, the
reaction chambers will be in a uniform array and which is
preferably a circular array. This provides an array that is easy to
service with a transport mechanism such as a turntable or carousel
and other devices such as an automatic manipulating system. It also
provides a continuous loop path for the carriers as opposed to a
linear array, which would have a beginning and an end such that the
carriers would have to be transported from the end back to the
beginning.
[0067] The system includes an array of reaction chambers suitable
in number to carry out the desired reactions, 202, 204, 206, 208,
210, 212, 214, 216, 218, 220, 222 and 224 shown in a circle. The
loaded support carriers are transported either manually or by
suitable conveyor or other means to the respective reaction
chambers 202, 204, 206, 208, 210, 212, 214, 216, 218, 220, 222 and
224. In a preferred arrangement, the system has 12 reaction
chambers and the support carriers that will be fed or loaded into
the chambers are either 12 in number or multiples thereof. The
carriers define an array of the solid supports as used herein. An
array may be defined by a single support (e.g. a 12.times.12
support) or by a plurality of the supports such as four 12.times.12
supports to define a 24.times.24 array.
[0068] The illustrated system includes an array of twelve reaction
chambers, but could have more or less. The reaction chambers are
identical, and only one will be described in detail. A reaction
chamber 202, as best illustrated in FIGS. 6 and 7, comprises a
generally cylindrical base 226 on which is mounted a cylindrical
vessel. The vessel may be a single cylindrical unit 228 or a double
unit including a second section or extension 230 and a removable
cover or closure 232. The extension 230 enables the vessel to be
enlarged to accommodate a large carrier rack 234 with multiple
carriers. The rack 234 is designed with vertically spaced
horizontal slots 236 to receive up to five carriers. This enables
the loading of four filled or loaded carriers and an empty carrier
to use in the redistribution steps as will be explained. An empty
carrier 108c is shown in the bottom slot of the rack.
[0069] The redistribution system 300 is disposed in the center of
and surrounded by the circular array of reaction chambers (FIGS. 2
and 3). Each of the reaction chambers is provided with a transfer
apparatus or unit 302, 304, 306, 308, 310, 312, 314, 316, 318, 320,
322 and 324 each of which includes means for receiving a carrier
rack and means for transferring the supports from carrier to
carrier. The redistribution system 300 also includes a conveyor or
transporting mechanism which, in the illustrated embodiment,
comprises a carousel or rotating table 326 having carrier holding
positions or stations such as a recess to receive and hold a
carrier aligned for each transfer unit. The carousel operates to
transport once-empty carriers from station to station for receiving
predetermined rows or columns of supports from a loaded
carrier.
[0070] Referring to FIGS. 8A-8D, associated with each reaction
chamber is a shuttle or support transfer apparatus as illustrated,
and designated generally at 300. The transfer devices are all
identical and only one of which 302 will be described in detail.
The transfer devices comprise a vertical support stand 328 having a
solid support transfer head 330 having a carrier to carrier
transfer mechanism therein. The solid support transfer mechanism
comprises a support member 332 mounted on a rotary member or shaft
334 having a reciprocating plunger with a plurality of transfer
punch pins 336 mounted thereon. The number of pins 336 are equal in
number to the solid support positions in a row or column in a
carrier. The pins are moved vertically by a suitable linear
actuator such as a pneumatic cylinder in shaft member 334. The
shaft 334 is rotated or indexed 90 degrees by a motor 338 through a
timing belt drive 340 to selectively position or orient the pins
336 for transferring a selected column or row of solid
supports.
[0071] The punch pins 336 are laterally positioned to a selected
one of a column or a row by a suitable drive mechanism such as a
motor 342 driving a belt or rack 344 (FIG. 8D). The pins 336 are
mounted on a moveable carriage or slide 346 (FIG. 8C) which is
connected to, and moved by, belt or chain 344. The power unit such
as a pneumatic cylinder operates to move the plunger vertically to
transfer the solid supports from a loaded carrier to a receiving
carrier. The plunger has a plurality of pins in lines corresponding
to the holding positions of the supports in the carriers.
[0072] As illustrated in FIG. 9A, a transfer unit 302 has an
elevator platform 350 mounted centrally within support 328 for
receiving a carrier rack 234. The elevator platform is raised and
lowered by a suitable means such as a stepping motor or air power
cylinder(not shown). Any number of suitable elevating mechanisms
may be utilized such as pneumatic or hydraulic cylinders,
electrical solenoid or a stepping motor device. For example, a
stepping motor drives a rack to raise and lower the platform. A
shuttle mechanism such as a pneumatic ram 356 is mounted on the
head and operative to shuttle or move carriers from the rack 324
onto a track positioned under the solid support transfer head
330.
[0073] The solid supports are loaded on or in the carriers in or
with predetermined arrays, preferably of rows and columns, which
may be equal or unequal. The loaded carriers are then transported
from the support loading system either manually or by suitable
means such as a conveyor or the like to the respective chemical
reaction chambers in the system where the chemical transformations
take place. The support carriers may have any suitable
configuration but are preferably square with a 12.times.12 array
sized and configured in order to cooperatively work with standard
microtiter trays. Thus, oligomers can be transferred directly from
supports in the carrier to microtiter trays for evaluation or
further processing. The typical microtiter trays have an 8.times.12
configuration, so that supports from two carriers would be
transferred to three microtiter trays.
[0074] In the illustrated system, as shown in FIGS. 9A and 9B, the
carousel 350 comprises a circular table top mounted for rotation
atop a pedestal 352. A drive motor, not shown, drives or steps the
top to position the carriers to the transfer positions. The
carousel top is preferably equipped with holders such as shown at
354-376 to receive and hold or register the carriers in position
for the transfer. The holders may take any suitable form but, are
preferably identical and only one, 354, will be described. The
holder 354 is secured to the carousel top and includes a track
formed of opposed groved side rails 378 and 380 in which a carrier
108 is slideably received and held in position to receive supports.
The holder may include stops or detents (not shown) to precisely
position the carrier.
[0075] In preparation for transfer of solid supports from carriers
from the reaction chamber, empty carriers will be placed on the
carousel in preparation for receiving supports from the loaded
carriers in the reaction chambers. In the illustrated embodiment,
an empty carrier 108c is initially loaded in the rack and
transferred from the rack to the holder 354 on carousel 326 when
preparing for the transfer. When the reaction and all processing is
complete and the supports are ready for transfer or redistribution,
the carriers containing the supports on which transformation has
occurred will be transported from the respective reaction chamber
to a position at the transfer station above the carriers on the
carousel. At this point, a transfer mechanism or implement
preferably in the form of a punch as previously described, will
move a selected one of either a column or row of supports from the
loaded carrier to the empty carrier. Hereinafter these carriers may
be designated the "donor carrier" and the "recipient carrier".
[0076] The solid supports may take any suitable form for optimally
supporting chemical transformations and for ease of handling in
conjunction with suitable carriers such as support carriers. The
support carriers may take any suitable form but are preferably of a
configuration which will easily receive the solid supports and hold
them in a fixed position to permit them to be handled or loaded
into reaction chambers and the solid supports transferred or
redistributed from carrier to carrier in preparation for each
chemical transformation. The loading of the carriers by the loading
system may be by robotics or other automatic means or it may be
manual.
[0077] In a preferred sequence of redistribution, row 1 will be
transferred from the loaded donor carrier at the first transfer
station 302 to row 1 in the recipient carrier at that station,
while row 2 is transferred from the loaded donor carrier at the
second transfer station 304 to row 2 in the recipient carrier at
that station, row 3 is transferred from the loaded donor carrier at
the third transfer station 306 to row 3 in the recipient carrier at
the third transfer station 306 and so on around the array. Thus,
when the first transfer has occurred, the first recipient carrier
will have a first row, the second recipient carrier will have a
second row, the third recipient carrier will have a third row, the
fourth recipient carrier will have a fourth row, and so on around
the array. These transfers are preferably made simultaneously but
may be made in sequence.
[0078] Thereafter, the carousel is operated by rotating it either
clockwise or counter clockwise, preferably clockwise, to move or
transport the carriers one station so that a second transfer can be
accomplished. At the same time the transfer punches at each station
is moved over one column or row in position to transfer the next
column. When the second transfer is initiated, assuming a clockwise
rotation, at the first transfer station 302, row 2 will be
transferred from the loaded donor carrier at the first transfer
station 302 to row 2 in the recipient carrier, while row 3 is
transferred from the loaded donor carrier at the second transfer
station 46 to row 3 in the recipient carrier, row 4 is transferred
from the loaded donor carrier at the third transfer station 302 to
row 4 in the recipient carrier at the third transfer station 306
and so on around the array. Thereafter, the carousel is indexed one
more position and column 3 is transferred at position 1, column 4
transferred at position 2, column 5 is transferred at position 3
and so on around the system. This continues until all columns or
rows in the donor carrier have been transferred to the columns in
the recipient carriers. At this stage each recipient carrier has
twelve individual columns and/or rows. These carriers are now moved
to the respective reaction chamber for a second chemical
transformation.
[0079] While this transformation is taking place, empty carriers
may then be loaded on the carousel in readiness for the next
transfer or redistribution. Preferably empty carriers are carried
along with the carriers in the rack. Upon completion of the next
chemical transformation, the carriers are moved from the reaction
chamber to the transfer stations and again, the previously
described sequence of transferring columns or rows is carried out.
In the event the two transformations is to occur for the particular
library at this juncture, the rows are transferred as opposed to
the columns. This can be carried out by indexing the donor carriers
of 90.quadrature. in the same direction or alternatively indexing
the transfer punches. Once this transfer has occurred, carriers are
again returned to the reaction chambers for the next or final
transformation. After the transformations are complete, the
position of the support in the system identifies the oligomer on
the support. At the end of this action, each of the target carriers
have 12 different columns that were donated from the 12 different
reaction stations. It will be appreciated that other sequences of
redistribution can be made so long as they are uniformly followed.
For example, all columns 1 can be transferred to a first recipient
carrier while all columns 2 can be transferred to a second
recipient carrier and so on.
[0080] In a system as described with 12 carriers with 12.times.12,
the result is 1,728 oligomer in the library. Thus, by knowing
exactly which chemical was in which of the 12 reaction chambers and
the sequence in which these solid supports were exposed to those
chemicals, allows one, at a subsequent time, to enter a particular
support by number and the position by column and row and know
exactly which chemical it has been exposed to.
[0081] With this system, if one wishes to carry out the process
with additional carriers such as, for example, a 24.times.24 array,
the process is carried out in the same manner. However, instead of
putting in only a single carrier in each reaction chamber, a stack
of four 12.times.12 carriers are loaded with supports plus an empty
carrier are placed in each chamber so that those 4 carriers give a
24.times.24 array which, in each 24.times.24 array of supports into
24 reaction chambers, yield 13,824 discrete compounds. In the
actual process after the first chemical reaction takes place, the
stack of 4 carriers in place in the reaction chambers are washed
and dried. When the first chemical transformation is completed and
it is ready to transfer to the donee or target carrier, the racks
from the chambers are loaded into the transfer stations. A first
empty carrier from each reaction chamber is put into place on the
carousel for transfer of columns or rows from a donor to a donee or
target carrier. Once these have been transferred as in the prior
described sequence as the transfer occurs, the carousel would
advance only to 12 positions, not 24. Now, at that point, the
carousel is backed up to position 1 again. The empty carriers are
then moved onto the carousel as the target carriers and then
indexed and columns 13-24 are transferred so that one continues
where one left off for the other 12 columns. This is repeated for
carriers three and four. The number of reaction chambers preferably
equal the number of carriers but at least equal the number of
arrays.
[0082] As is apparent from the above-described general system,
first of all, the carousel type of array is a preferred system
because it is a continuous system. On the other hand, while a
linear system may be preferred in some instances, a linear system
would require that a carrier at the end of the line be brought back
to the beginning of the line to continue.
[0083] It will also be apparent that, with this system, multiples
of 12 carriers can be handled even with only a 12 position
carousel. Where the carousel has a position for each reaction
chamber, the carousel need only move through 12 positions for a
complete transfer. A 24.times.24 array produces 13,824 discrete
compounds.
[0084] Referring to FIG. 10, an exemplary solid support 150 is
illustrated with a somewhat cylindrical configuration with
hemispherical ends. While the supports may have any suitable
configuration, this configuration was selected as being easier to
move through the carriers without the likelihood of hang up. It
also provides more support area than a spherical support.
[0085] Referring to FIG. 11A, a exemplary solid support carrier 152
is illustrated with a square configuration and a twelve by twelve
array of holding positions in the form of through openings 154.
These holding positions or openings are preferably formed with
straight sides but may have slightly converging diverging walls so
that solid supports are frictionally gripped at or by the center of
the opening, but are allowed to pass through with a little force.
FIG. 13B illustrates a sectional view on lines 13B of FIG. 11A
showing details of construction of the carrier and support.
[0086] Referring to FIGS. 12A-12C, a detailed illustration of a
pair of support carriers 108c and 108d and the transfer mechanism
transferring supports from a donor carrier to a target carrier is
illustrated. As illustrated a plurality of supports 150 are shown
with a somewhat cylindrical configuration with hemispherical ends.
The carriers, as previously described are configured with a grid
like construction with walls forming a plurality of through
openings with walls to grip and holds the solid supports in
position. As shown in 14A, a loaded carrier 108d is supported in a
track 182 above an empty lower carrier 108c. A transfer punch
mechanism 332 is disposed above the carriers with a row of punch
pins 336 aligned with a row or column of the supports in the upper
carrier 108d.
[0087] The punch is activated as shown in FIG. 14B whereby the
plurality of punch pins move downward and engage and move or
transfer the plurality of supports from the upper carrier to the
lower carrier. The punch is then retracted as shown in FIG. 14C
leaving the row or column of solid supports in the lower
carrier.
[0088] Referring to FIG. 13, a schematic illustration of an
exemplary control and power system for the present system is
illustrated and designated generally by the numeral 400. A low
voltage D.C. power supply 402 provides power to the three main
components of the system to power the various motors, valves and
other components. A source of pressurized air 404 supplies air to
the support loading station and to power the support transfer
stations. This pressurized air powers the pneumatic motors or
cylinders that power or operate the various punches, shuttles and
other components of these systems. A control computer or CPU 404 is
programmed to control the various valves, switches and other
components and functions of the system.
[0089] Referring to FIG. 14, a carrier arrangement of four
12.times.12 carriers 108e, 108f, 108g and 108h for providing a
24.times.24 solid support array for the present system is
illustrated and designated generally by the numeral 410. Thus, a
carrier or an array can consist of one or a multiple individual
carriers. In addition, it will be appreciated that where multiple
carriers make up an array, the individual carriers, when unloaded,
become second or donee carriers. In the illustrated example, the
donee carriers need be only be one fourth in number of the loaded
carriers. The present invention, as described above, is preferably
carried out with symmetrical arrays. However, it will be
appreciated that it can be carried out utilizing unsymmetrical
arrays.
[0090] As will become clear to those skilled in the art, the
techniques described here can be extended to synthesize
combinatorial libraries in which more than three combinatorial
steps are employed and different number of monomers are applied in
each chemical transformation step. In such cases it may be
difficult to visualize and describe the sequence of positional
transformations of solid supports among the series of arrays. A
computer algorithm can be designed which takes as input the goals
of a synthetic experiment: namely, the desired number of
combinatorial steps and the desired number of monomers used in each
combinatorial step. The algorithm can then generate a map of the
protocol required to satisfy the experimental goal. This map would
contain the same information as that given in the figures used
herein. In the event that the experimental goal can not be
satisfied the algorithm would suggest a protocol which would
achieve a result as close as possible to the desired result.
[0091] The algorithm could be constructed to generate only those
protocols that are consistent with a set of constraints imposed by
an actual laboratory apparatus, for example, a fixed number of
reaction vessels, carrier racks of a given dimension, and so forth.
Such a computer algorithm would be useful for the practical
application of the techniques disclosed herein. As a refinement of
this method, such a computer algorithm could be designed to
generate machine instructions for an automated synthetic apparatus
which would perform the necessary chemical steps and positional
transformations required to synthesize the desired combinatorial
library.
[0092] The methods described in the body of the invention may be
used to produce non-peptide, low molecular weight organic compound
libraries. The synthetic chemistry protocols are more complex in
the syntheses of many of these compounds than those utilized to
construct peptide libraries. Additionally, there are no general
methods available to directly sequence the structure of most of
these compounds. Thus, the ease by which a library is decoded using
the method described herein renders it suitable for the synthesis
of low molecular weight compounds. The synthesis of a heterocyclic
library can be demonstrated.
[0093] While we have illustrated and described our invention by
means of specific embodiments, it will be appreciated that numerous
changes and modifications can be made therein without departing
from the spirit and scope of the invention as defined in the
appended claims.
* * * * *