Compounds And Related Methods For Treatment Of Neurodegenerative Diseases

Abstract

Aspects of the invention pertain to chemical compounds, therapeutic compositions, and methods for treating neurodegenerative diseases, in particular, neurodegenerative diseases associated with abnormal accumulation of protein tau.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a divisional application of U.S. patent application Ser. No. 14/271,177, filed May 6, 2014, and now allowed, which claims the benefit of U.S. Provisional Application Ser. No. 61/819,701, filed May 6, 2013, which are hereby incorporated by reference in its entireties.

BACKGROUND

[0002] Intracellular aggregation of abnormal species of phosphorylated tau (protein tau) is a major pathologic feature of a family of neurodegenerative diseases collectively referred to as the tauopathies. Tau normally functions to stabilize microtubules in neurons; however, it pathologically aggregates more than 15 neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease. The most common tauopathy is Alzheimer's disease, in which paired helical filaments (PHFs) of mis-folded protein tau aggregates in neurofibrillary tangles, in dystrophic neuritis of senile plaques, and in cell processes in the neuropil. Abnormal accumulation of protein tau is closely linked with postsymptomatic progression in Alzheimer's disease. Abnormal accumulation of protein tau in the cytoplasm of neuronal and glial cells also represents major structural hallmarks in the pathology of Pick's disease, corticobasal degeneration, and progressive supranuclear palsy.

[0003] At present, researchers on the development of therapeutics for tauopathies focus primarily on agents that prevent abnormal phosphorylation or aggregation of tau proteins. However, it has been discovered that while aggregation of hyperphosphorylated protein tau is visible evidence of tauopathies, these neurofibrillary tangles appear to be less toxic than soluble intermediates of protein tau. High levels of tau intermediates, particularly aberrant tau species failed to be cleared from cells, cause cognitive dysfunction in AD and tauopathies. Therefore, agents that degrade or destabilize tau intermediates, clear aberrant tau species from cells, or otherwise reduce intracellular tau levels, are promising therapeutics for AD and tauopathies.

[0004] Existing therapeutics for the treatment tauopathies (such as AD) only demonstrate limited efficacy; as such, additional therapeutics for the treatment of tauopathies are needed.

BRIEF SUMMARY

[0005] Aspects of the invention provide chemical compounds for treating neurodegenerative diseases, in particular, neurodegenerative diseases associated with abnormal accumulation of protein tau.

[0006] One aspect of the invention provides a method of reducing intracellular tau levels comprising administering, to cells comprising protein tau, an effective amount of compound A:

##STR00001##

[0007] In another aspect, the invention provides a method of reducing intracellular tau levels comprising administering, to cells comprising protein tau, an effective amount of compound B:

##STR00002##

[0008] In some embodiments of aspects of the invention, the cells are in a subject, such as a human, in need of treatment for a neurodegenerative disease. The neurodegenerative disease may be a tauopathy. In some embodiments, the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, frontotemporal dementia, frontotemporal dementia with Parkinsonism, frontotemporal lobe dementia, pallidopontonigral degeneration, progressive supranuclear palsy, multiple system tauopathy, multiple system tauopathy with presenile dementia, Wilhelmsen-Lynch disease, Pick's disease, or Pick's disease-like dementia. In one embodiment, the neurodegenerative disease is Alzheimer's disease.

[0009] In additional aspects, the invention provides pharmaceutical compositions comprising any of compounds A, B, and combinations thereof.

BRIEF DESCRIPTION OF THE DRAWINGS

[0010] FIG. 1 shows a western blot analysis of phosphorylated tau following Palmadorin M and Beauvericin treatment in HeLa cells transfected with (A) wild type human tau and (B) mutant P301L human tau.

BRIEF DESCRIPTION OF THE SEQUENCES

[0011] SEQ ID NO:1 is an amino acid sequence of a tau protein isoform (tau 352) useful according to aspects of the invention.

[0012] SEQ ID NO:2 is an amino acid sequence of a tau protein isoform (tau 441) useful according to aspects of the invention.

[0013] SEQ ID NO:3 is an amino acid sequence of a tau protein isoform (tau 383) useful according to aspects of the invention.

[0014] SEQ ID NO:4 is an amino acid sequence of a tau protein isoform (tau 758) useful according to aspects of the invention.

[0015] SEQ ID NO:5 is an amino acid sequence of a tau protein isoform (tau 776) useful according to aspects of the invention.

[0016] SEQ ID NO:6 is an amino acid sequence of a tau protein isoform (tau 412) useful according to aspects of the invention.

DETAILED DESCRIPTION

[0017] Aspects of the invention provide chemical compounds and compositions for treating neurodegenerative diseases, in particular, neurodegenerative diseases associated with abnormal accumulation of protein tau.

[0018] In one aspect, the invention provides compounds A and B, or salts thereof:

##STR00003##

[0019] In one embodiment, the invention provides an isolated or substantially pure compound A, or a salt thereof,

##STR00004##

[0020] In one embodiment, the invention provides an isolated or substantially pure compound B, or a salt thereof,

##STR00005##

[0021] In certain embodiments, the invention pertains to the uses of compound A (palmadorin M) and/or compound B (beauvericin), or salts thereof, for treating neurodegenerative diseases, in particular, neurodegenerative diseases associated with abnormal accumulation of protein tau.

[0022] In some embodiments, the compounds of the present invention are at least 75% pure, preferably at least 90% pure, more preferably are more than 95% pure, and most preferably are more than 99% pure (substantially pure). The compounds of the present invention can also be synthesized.

[0023] The compounds and compositions of the present invention, through administration to a subject, are useful for treating or ameliorating neurodegenerative diseases or conditions, in particular, neurodegenerative diseases or conditions associated with abnormally high levels of protein tau and/or abnormal accumulation of protein tau in neurons. In some embodiments, the compounds and compositions are useful to treat or ameliorate Alzheimer's disease or Parkinson's disease.

[0024] In one aspect, the invention provides methods for treating or ameliorating a neurodegenerative disease or condition, particularly a disease or condition associated with abnormally high levels of protein tau and/or abnormal accumulation of protein tau in neurons, wherein the method comprises administering, to a subject in need of such treatment, an effective amount of a composition comprising a compound selected from compound A and compound B, or salts thereof.

[0025] Another aspect of the invention provides a method of reducing intracellular tau levels comprising administering, to cells comprising protein tau, an effective amount of compound A:

##STR00006##

[0026] In another aspect, the invention provides a method of reducing intracellular tau levels comprising administering, to cells comprising protein tau, an effective amount of compound B:

##STR00007##

[0027] In yet another aspect, the invention provides a method of reducing intracellular tau levels comprising administering, to cells comprising protein tau, an effective amount of compounds selected from compound A (Palmadorin M) and compound B (Beauvericin), and combinations thereof.

[0028] The term "subject," as used herein, describes an organism, including mammals, to which treatment with the compositions and compounds according to the subject invention can be administered. Mammalian species that can benefit from the disclosed methods of treatment include, but are not limited to, apes, chimpanzees, orangutans, humans, monkeys; and other animals such as dogs, cats, horses, cattle, pigs, sheep, goats, chickens, mice, rats, guinea pigs, and hamsters. Typically, the subject is a human.

[0029] The term "tau protein" or any grammatical variation thereof (e.g., protein tau and tau etc.), as used herein, refers generally to any protein of the microtubule-associated tau protein family. Members of the tau family share the common features of a characteristic N-terminal segment, sequences of approximately 50 amino acids inserted in the N-terminal segment, a characteristic tandem repeat region consisting of 3 or 4 tandem repeats of 31-32 amino acids, and a C-terminal tail. Tau proteins of the present invention may be in a form of soluble tau intermediates, functional, aberrant, abnormally-truncated, mis-folded or mis-processed tau, and phosphorylated tau.

[0030] In some embodiments, tau protein of the invention is of mammalian origin, and more preferably, of human origin. Specifically, tau proteins of the subject invention include microtubule-associated protein translated from the human chromosomal sequence of GenBank Accession No. AH005895 and naturally-occurring mammalian variants or isoforms thereof. Six human brain tau isoforms are currently known, including tau352 (GenBank Accession No. NP.sub.--058525) (SEQ ID NO:1), tau441 (GenBank Accession No. NP.sub.--005901) (SEQ ID NO:2), tau383 (GenBank Accession No. NP.sub.--058518) (SEQ ID NO:3), tau758 (GenBank Accession No. NP.sub.--058519) (SEQ ID NO:4), tau776 (GenBank Accession No. NP.sub.--001116538) (SEQ ID NO:5), and tau412 (GenBank Accession No. NP.sub.--001116539) (SEQ ID NO:6).

[0031] The term "treatment" or any grammatical variation thereof (e.g., treat, treating and treatment etc.), as used herein, includes but is not limited to, ameliorating or alleviating a symptom of a disease or condition, reducing, suppressing, inhibiting, lessening, or affecting the progression, severity, and/or scope of a condition, chance of re-occurrence or returning of a disease after a remission. For instance, the term "treatment" includes (i) ameliorating a symptom associated with a neurodegenerative disease in a patient diagnosed with the neurodegenerative disease; and/or (ii) relieving (such as attenuating the progress of) or remedying a neurodegenerative disease in a patient diagnosed with the neurodegenerative disease.

[0032] In some embodiments, the treatment methods of the present invention reduce tau levels and/or improve tau clearance. Normal, functional tau is less affected by clearance pathways in the cell than aberrant tau. In one embodiment, the treatment methods of the present invention modulate tau clearance by selectively targeting abnormal tau.

[0033] In an embodiment, the therapeutic composition is administered to a human subject who has symptoms of, or is diagnosed with, a neurodegenerative disease. In some embodiments, the therapeutic composition is administered to a human subject who has symptoms of, or is diagnosed with, a neurodegenerative disease associated with abnormal accumulation of protein tau. For instance, the therapeutic composition is administered to a human subject who has elevated levels of soluble protein tau and/or hyperphosphorylated protein tau in the nervous system, such as in the brain or cytoplasm of neuronal and glial cells. In addition, the therapeutic composition is administered to a human subject who exhibits pathologic features such as neurofibrillary tangles or senile plaques in neuronal cells and/or cell processes. In a specific embodiment, the therapeutic composition is administered to a human subject who has symptoms of, or is diagnosed with, Alzheimer's disease.

[0034] The identification of subjects who are in need of treatment for a neurodegenerative disease is well within the knowledge and ability of one skilled in the art. By way of example, a clinician skilled in the art can readily identify, by the use of clinical tests, neurologic and physical examination, and medical/family history, those patients who are suffering from a neurodegenerative disease as well as those who are predisposed to developing a neurodegenerative disease and thus readily determine if an individual is in need of treatment. For instance, neurofibrillary tangles or senile plaques present in neuronal cells and/or cell processes can be determined using electron microscopy (EM) or other clinical techniques known in the art. In addition, spinal fluid or cerebral fluid samples or tissues samples from hippocampal tissue or frontal cortex tissue samples may be obtained from a subject and levels of protein tau present in the samples can be determined using routine techniques such as enzyme-linked immunosorbant assay (ELISA), western blot, and immunological assays.

[0035] The compounds and compositions of the present invention can be administered to the subject being treated by standard routes, including oral, inhalation, or parenteral administration including intravenous, subcutaneous, topical, transdermal, intradermal, transmucosal, intraperitoneal, intramuscular, intracapsular, intraorbital, intracardiac, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection, infusion, and electroporation, as well as co-administration as a component of any medical device or object to be inserted (temporarily or permanently) into a subject. In a one embodiment, the compounds and compositions of the subject invention are administered orally.

[0036] The term "effective amount" or "therapeutically effective amount," as used herein, refers to an amount that is capable of treating or ameliorating a disease or condition or otherwise capable of producing an intended therapeutic effect. For instance, the effective amount of the compounds and compositions of the present invention is an amount capable of reducing levels of protein tau in a subject. In certain embodiments, the effective amount enables a 5%, 25%, 50%, 75%, 90%, 95%, 99% and 100% reduction of levels of protein tau (e.g. soluble protein tau intermediates and/or aberrant protein tau) in a subject.

[0037] The amount of the therapeutic or pharmaceutical composition which is effective in treatment of a neurodegenerative disease will depend on the nature of the disease, condition or disorder and can be determined by standard clinical techniques. Illustratively, dosage levels of the administered active ingredients can be: intravenous, 0.01 to about 20 mg/kg; intraperitoneal, 0.01 to about 100 mg/kg; subcutaneous, 0.01 to about 100 mg/kg; intramuscular, 0.01 to about 100 mg/kg; orally 0.01 to about 200 mg/kg and preferably about 1 to 100 mg/kg; intranasal instillation, 0.01 to about 20 mg/kg; and aerosol, 0.01 to about 20 mg/kg of animal (body) weight.

[0038] Once improvement of the subject's condition has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, may be reduced as a function of the symptoms to a level at which the improved condition is retained. When the symptoms have been alleviated to the desired level, treatment should cease. Subjects may however require intermittent treatment on a long-term basis upon any recurrence of disease symptoms.

[0039] In addition, in vitro assays may optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the formulation/composition will also depend on the route of administration, and the seriousness of the disease, condition or disorder, and should be decided according to the judgment of the practitioner and each patient's circumstances. Effective doses may be extrapolated from dose-response curves derived from in vitro or animal model test systems.

[0040] The compounds and compositions of the present invention can be used to treat or ameliorate neurodegenerative diseases including, but not limited to, Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis (ALS), Huntington's disease, multiple sclerosis, Pick's disease, fronto temporal dementia, cortico-basal degeneration, progressive supranuclear palsy, Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, and Kuru.

[0041] The compounds and compositions of the present invention can also be used to treat or ameliorate neurodegenerative diseases including, but not limited to, Down's syndrome, Argyrophilic grain disease, parkinsonism dementia complex of Guam, non-Guamanian motor neurone disease with NFT, Niemann-Pick disease type C, subacute sclerosing panencephalitis, postencephalitic parkinsonism, dementia pugilistica, myotonic dystrophy, prion protein amyloid antipathy, and Hallervorden-Spatz disease.

[0042] The compounds and compositions of the present invention are particularly useful to treat or ameliorate a neurodegenerative disease involving tau pathologies (i.e., tauopathies) including, but not limited to, Alzheimer's disease, Parkinson's disease, frontotemporal dementia, frontotemporal dementia with Parkinsonism, frontotemporal lobe dementia, pallidopontonigral degeneration, progressive supranuclear palsy, multiple system tauopathy, multiple system tauopathy with presenile dementia, Wilhelmsen-Lynch disease, Pick's disease, and Pick's disease-like dementia.

[0043] Specifically, the compounds and compositions of the present invention are particularly useful to treat or ameliorate a disease or condition arising, at least in part, from abnormally high levels of protein tau in the nervous system, such as in cytoplasm of neuronal and glial cells and in neuronal and glial cell processes. Thus, the subject invention is particularly useful for treatment of neurodegenerative diseases and disorders, in which reduction of levels of protein tau in the nervous system would be beneficial.

[0044] In addition, the compounds and compositions of the subject invention are useful for alleviating or attenuating symptoms arising from or associated with neurodegenerative diseases, including cognitive dysfunction, impaired memory, impaired mental capacities, emotional disturbances, speech dysfunction, incontinence, tremor, postural instability, rigidity or stiff movement, muscle paralysis, and pain.

[0045] In additional aspects, the invention provides pharmaceutical compositions comprising a therapeutically effective amount of any of compounds A and/or B and a pharmaceutically acceptable carrier or adjuvant.

[0046] The terms "pharmaceutically acceptable", "physiologically tolerable" and grammatical variations thereof, as used herein, include compositions, carriers, diluents and reagents, are used interchangeably, and represent that the materials are capable of administration to or upon a subject such as mammal.

[0047] The term "carrier" refers to an adjuvant, excipient, or vehicle with which the compound is administered. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum oil such as mineral oil, vegetable oil such as peanut oil, soybean oil, and sesame oil, animal oil, or oil of synthetic origin. Particularly preferred pharmaceutical carriers for treatment of or amelioration of a neurodegenerative disease are carriers that can penetrate the blood/brain barrier.

[0048] Suitable carriers also include ethanol, dimethyl sulfoxide, glycerol, silica, alumina, starch, sorbitol, inosital, xylitol, D-xylose, mannitol, powdered cellulose, microcrystalline cellulose, talc, colloidal silicon dioxide, calcium carbonate, calcium phosphate, calcium aluminium silicate, aluminium hydroxide, sodium starch phosphate, lecithin, and equivalent carriers and diluents. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.

[0049] Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. The therapeutic composition, if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.

[0050] The amount of active ingredient (i.e., one or more of compounds A or B) that may be combined with the carrier materials to produce a single dosage form will vary, depending on the type of the condition and the subject to be treated. In general, a therapeutic composition contains from about 5% to about 95% active ingredient (w/w). More specifically, a therapeutic composition contains from about 20% (w/w) to about 80% or about 30% to about 70% active ingredient (w/w).

[0051] The compounds and compositions can be formulated according to known methods for preparing pharmaceutically useful compositions. Formulations are described in detail in a number of sources which are well known and readily available to those skilled in the art. For example, Remington's Pharmaceutical Science by E. W. Martin describes formulations which can be used in connection with the present invention. In general, the compositions of the present invention will be formulated such that an effective amount of the bioactive compound(s) is/are combined with a suitable carrier in order to facilitate effective administration of the composition.

[0052] The therapeutic or pharmaceutical compositions of the invention can also be formulated as neutral or salt forms. Pharmaceutically acceptable salts include those formed with free amino groups such as those derived from hydrochloric, phosphoric, acetic, oxalic, tartaric acids, etc., and those formed with free carboxyl groups such as those derived from sodium, potassium, ammonium, calcium, ferric hydroxides, isopropylamine, triethylamine, 2-ethylamino ethanol, histidine, procaine, etc.

[0053] The preparation of a pharmacological composition that contains active ingredients dissolved or dispersed therein is well understood in the art and need not be limited based on formulation. Typically such compositions are prepared as injectables, either as liquid solutions or suspensions; however, solid forms suitable for solution, or suspensions, in liquid prior to use also can be prepared. The preparation also can be emulsified, such as oil-in-water emulsion.

[0054] The compounds and compositions of the present invention in prescription amounts can be readily made into any form of drug, suitable for administering to humans or other animals. Suitable forms include, for example, tinctures, decoctions, and dry extracts. These can be taken orally, applied through venous injection, mucous membranes or inhalation. The active ingredient(s) can also be formulated into capsules, powder, pallets, pastille, suppositories, oral solutions, pasteurized gastroenteric suspension injections, small or large amounts of injection, frozen powder injections, pasteurized powder injections and the like.

EXAMPLES

[0055] All patents, patent applications, provisional applications, and publications referred to or cited herein are incorporated by reference in their entirety, including all figures and tables, to the extent they are not inconsistent with the explicit teachings of this specification.

[0056] Following are examples that illustrate procedures for practicing the invention. These examples should not be construed as limiting. All percentages are by weight and all solvent mixture proportions are by volume unless otherwise noted.

Example 1

Palmadorin M Extraction and Characterization

[0057] 600 g of freeze-dried Antarctic nudibranchs, Austrodoris kerguelenensis, collected by hand via SCUBA off the Palmer Station in the Western Antarctic Peninsula (3-40 m depth range), were first extracted by DCM/MeOH (1:1) then EtOAc/H.sub.2O (1:1). Both resulting extracts were combined and fractionated by normal phase MPLC using gradient conditions from 100% hexanes to 100% ethyl acetate to 100% methanol. The separation provided 10 MPLC fractions. The last 8 fractions were combined and purified by reversed-phase semi-preparative HPLC (40-100% MeOH--H.sub.2O over 70 minutes) to provide 16 fractions. Fraction 13 (47 min) yielded 10.1 mg of palmadorin M (Maschek J. A., 2011 et Maschek J. A. et al., 2012).

##STR00008##

Colorless oil; [.alpha.].sub.D.sup.20-18 (c 0.1, CHCl.sub.3); UV (MeOH) .lamda.max (.epsilon.) 230 (4.38) nm; IR (thin film) 3429 (br), 2935, 1696, 1645, 1214 cm.sup.-1; .sup.1H NMR (500 MHz, CDCl3) 5.72 (1H, s, H-14), 4.93 (1H, s, H-2'), 4.71 (1H, t, H-17b), 4.52 (1H, t, H-17a), 3.83 (2H, m, H.sub.2-1'), 3.83 (2H, m, H.sub.2-3'), 2.18 (1H, m, H-7b), 2.15 (3H, s, H.sub.3-16), 2.04 (1H, m, H-7a), 2.04 (1H, m, H-12b), 1.87 (1H, m, H-12a), 1.70 (1H, m, H-11b), 1.63 (1H, m, H-2b), 1.62 (1H, m, H-6b), 1.53 (1H, m, H-1b), 1.51 (1H, m, H-9), 1.47 (1H, m, H-11a), 1.44 (1H, m, H-2a), 1.42 (1H, m, H-3b), 1.29 (1H, m, H-6a), 1.28 (1H, m, H-5), 1.18 (1H, m, H-3a), 1.06 (1H, m, H-1a), 0.92 (3H, s, H.sub.3-20), 0.88 (3H, s, H.sub.3-19), 0.81 (3H, s, H.sub.3-18); .sup.13C NMR (125 MHz, CDCl3) 166.8 (C-15), 163.2 (C-13), 148.7 (C-8), 114.5 (C-14), 109.9 (C-17), 74.2 (C-2'), 62.3 (C-1'), 62.3 (C-3'), 57.8 (C-9), 45.8 (C-5), 42.6 (C-3), 39.8 (C-12), 38.0 (C-10), 36.7 (C-1), 33.4 (C-19), 33.2 (C-4), 31.5 (C-7), 24.7 (C-11), 23.5 (C-6), 22.3 (C-20), 22.1 (C-18), 19.4 (C-16), 19.1 (C-2); HRESIMS m/z 401.2648 [M+Na].sup.+ (C.sub.23H.sub.38NaO.sub.4 requires 401.2668).

Example 2

Beauvericin Extraction and Characterization

[0058] Fungi Collection, Culture Preparation, Isolation and Scale Up:

[0059] Segments of approximately 1-2 mm.sup.2 of mangrove samples were plated on malt extract freshwater agar. Fungal growth was examined every day for two weeks and then twice a week for at least one month for isolation of pure fungal strain. Pure fungal cultures were grown for scale up to 2 L total volume in liquid medium which contained 1% w/v glucose, 0.1% w/v yeast extract and 0.2% w/v peptone (3 weeks) for extraction, separation and pure metabolite identification (Calcul et al. 2013)

[0060] Beauvericin:

[0061] 2.3 g from a freeze-dried scale up of fungus strain collection # EG09-15B-2, isolated from the Florida Everglades bark of Coccoloba uvifera, was extracted by MeOH. The methanolic extract was separated by reverse phase MPLC using gradient from H.sub.2O/10% MeOH to 100% MeOH to give 6 fractions. Fraction 5 was selected to be further chromatographied by normal phase MPLC using a gradient from 100% hexane to 100% EtOAc and provided 6 fractions. Fraction 4 was purified on reverse phase semi-preparative HPLC using isocratic H.sub.2O/55% ACN yielding 206.2 mg of Beauvericin (trimer). (Beau J. 2012)

##STR00009##

Colorless film; .sup.1H NMR (500 MHz, CDCl3) 7.26-7.14 (3H, m, H-12), 7.26-7.14 (6H, m, H-11), 7.26-7.14 (6H, m, H-10), 5.62 (3H, s, H-6), 4.81 (3H, d, H-3), 3.39 (3H, dd, H-8a), 3.03 (9H, s, H-7), 2.93 (3H, dd, H-8b), 1.93 (3H, dq, H-13), 0.78 (9H, d, H-14), 0.35 (9H, d, H-15); .sup.13C NMR (125 MHz, CDCl3) 170.0 (C-1), 169.9 (C-4), 136.4 (C-9), 128.7 (C-11), 128.5 (C-10), 126.8 (C-12), 75.7 (C-6), 56.8 (C-3), 34.7 (C-7), 31.9 (C-8), 29.7 (C-13), 18.4 (C-14), 17.1 (C-15); LRESIMS m/z 784.4 [M+H].sup.+--Note: the .sup.1H and .sup.13C NMR data matched to the data from the literature (Gupta, S. et al. 1991);

Example 3

Palmadorin M and Beauvericin Preferentially Reduce Phosphorylated Tau

[0062] Compounds effects on tau activity/level were determine by a previously described method (Jinwal et al J. Neurosci. 2009 Sep. 30; 29(39):12079-88). In brief, human tau transfected HeLa Cells were treated with Compounds for 24 hours. Cells were harvested by using MPER reagent containing protease inhibitor and phosphatase inhibitor. Samples were analyzed by western blot. pS199-202 antibody was used to detect phospho tau level. Total tau levels were detected by tau H-150 &/or tau 46 antibodies.

[0063] HeLa cells were transfected with wild-type human tau (A) and mutant P301L human tau (B) (FIG. 1). After 24 hours, cells were treated with either palmadorin M or beauvericin for 24 hours. Western blot analysis of samples showed potent reduction in phosphorylated (pS199-202) wild type and mutant P301L tau at various doses of palmadorin M and beauvericin. Tau H-150 antibody tested for N-terminal tau showed increase in tau level. Tau 46 antibody tested for C-terminal tau showed moderate change in tau level.

[0064] It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application and the scope of the appended claims. In addition, any elements or limitations of any invention or embodiment thereof disclosed herein can be combined with any and/or all other elements or limitations (individually or in any combination) or any other invention or embodiment thereof disclosed herein, and all such combinations are contemplated with the scope of the invention without limitation thereto.

REFERENCES

[0065] Maschek J. A. "Chemical Investigation of the Antarctic Marine Invertebrates Austrodoris kerguelenensis & Dendrilla membranosa and the Antarctic Red Alga Gigartina skottsbergii" Ph.D. Thesis, Department of Chemistry, College of Art and Sciences, University of South Florida, Tampa, Fla., USA, 7 Jun. 2011. [0066] Maschek J. A. 2012, Tetrahedron, 9095-9104. [0067] Beau J. "Drug Discovery from Floridian Mangrove Endophytes" PhD. Thesis, Department of Chemistry, College of Art and Sciences, University of South Florida, Tampa, Fla., USA, 12 Jul. 2012. [0068] Gupta S. et al. Mycopathologia, 1991, 185-189 [0069] Calcul L. et al. Mar. Drugs, 2013, 5036-5050.

Sequence CWU 1

1

61352PRTHomo sapiens 1Met Ala Glu Pro Arg Gln Glu Phe Glu Val Met Glu Asp His Ala Gly 1 5 10 15 Thr Tyr Gly Leu Gly Asp Arg Lys Asp Gln Gly Gly Tyr Thr Met His 20 25 30 Gln Asp Gln Glu Gly Asp Thr Asp Ala Gly Leu Lys Ala Glu Glu Ala 35 40 45 Gly Ile Gly Asp Thr Pro Ser Leu Glu Asp Glu Ala Ala Gly His Val 50 55 60 Thr Gln Ala Arg Met Val Ser Lys Ser Lys Asp Gly Thr Gly Ser Asp 65 70 75 80 Asp Lys Lys Ala Lys Gly Ala Asp Gly Lys Thr Lys Ile Ala Thr Pro 85 90 95 Arg Gly Ala Ala Pro Pro Gly Gln Lys Gly Gln Ala Asn Ala Thr Arg 100 105 110 Ile Pro Ala Lys Thr Pro Pro Ala Pro Lys Thr Pro Pro Ser Ser Gly 115 120 125 Glu Pro Pro Lys Ser Gly Asp Arg Ser Gly Tyr Ser Ser Pro Gly Ser 130 135 140 Pro Gly Thr Pro Gly Ser Arg Ser Arg Thr Pro Ser Leu Pro Thr Pro 145 150 155 160 Pro Thr Arg Glu Pro Lys Lys Val Ala Val Val Arg Thr Pro Pro Lys 165 170 175 Ser Pro Ser Ser Ala Lys Ser Arg Leu Gln Thr Ala Pro Val Pro Met 180 185 190 Pro Asp Leu Lys Asn Val Lys Ser Lys Ile Gly Ser Thr Glu Asn Leu 195 200 205 Lys His Gln Pro Gly Gly Gly Lys Val Gln Ile Val Tyr Lys Pro Val 210 215 220 Asp Leu Ser Lys Val Thr Ser Lys Cys Gly Ser Leu Gly Asn Ile His 225 230 235 240 His Lys Pro Gly Gly Gly Gln Val Glu Val Lys Ser Glu Lys Leu Asp 245 250 255 Phe Lys Asp Arg Val Gln Ser Lys Ile Gly Ser Leu Asp Asn Ile Thr 260 265 270 His Val Pro Gly Gly Gly Asn Lys Lys Ile Glu Thr His Lys Leu Thr 275 280 285 Phe Arg Glu Asn Ala Lys Ala Lys Thr Asp His Gly Ala Glu Ile Val 290 295 300 Tyr Lys Ser Pro Val Val Ser Gly Asp Thr Ser Pro Arg His Leu Ser 305 310 315 320 Asn Val Ser Ser Thr Gly Ser Ile Asp Met Val Asp Ser Pro Gln Leu 325 330 335 Ala Thr Leu Ala Asp Glu Val Ser Ala Ser Leu Ala Lys Gln Gly Leu 340 345 350 2441PRTHomo sapiens 2Met Ala Glu Pro Arg Gln Glu Phe Glu Val Met Glu Asp His Ala Gly 1 5 10 15 Thr Tyr Gly Leu Gly Asp Arg Lys Asp Gln Gly Gly Tyr Thr Met His 20 25 30 Gln Asp Gln Glu Gly Asp Thr Asp Ala Gly Leu Lys Glu Ser Pro Leu 35 40 45 Gln Thr Pro Thr Glu Asp Gly Ser Glu Glu Pro Gly Ser Glu Thr Ser 50 55 60 Asp Ala Lys Ser Thr Pro Thr Ala Glu Asp Val Thr Ala Pro Leu Val 65 70 75 80 Asp Glu Gly Ala Pro Gly Lys Gln Ala Ala Ala Gln Pro His Thr Glu 85 90 95 Ile Pro Glu Gly Thr Thr Ala Glu Glu Ala Gly Ile Gly Asp Thr Pro 100 105 110 Ser Leu Glu Asp Glu Ala Ala Gly His Val Thr Gln Ala Arg Met Val 115 120 125 Ser Lys Ser Lys Asp Gly Thr Gly Ser Asp Asp Lys Lys Ala Lys Gly 130 135 140 Ala Asp Gly Lys Thr Lys Ile Ala Thr Pro Arg Gly Ala Ala Pro Pro 145 150 155 160 Gly Gln Lys Gly Gln Ala Asn Ala Thr Arg Ile Pro Ala Lys Thr Pro 165 170 175 Pro Ala Pro Lys Thr Pro Pro Ser Ser Gly Glu Pro Pro Lys Ser Gly 180 185 190 Asp Arg Ser Gly Tyr Ser Ser Pro Gly Ser Pro Gly Thr Pro Gly Ser 195 200 205 Arg Ser Arg Thr Pro Ser Leu Pro Thr Pro Pro Thr Arg Glu Pro Lys 210 215 220 Lys Val Ala Val Val Arg Thr Pro Pro Lys Ser Pro Ser Ser Ala Lys 225 230 235 240 Ser Arg Leu Gln Thr Ala Pro Val Pro Met Pro Asp Leu Lys Asn Val 245 250 255 Lys Ser Lys Ile Gly Ser Thr Glu Asn Leu Lys His Gln Pro Gly Gly 260 265 270 Gly Lys Val Gln Ile Ile Asn Lys Lys Leu Asp Leu Ser Asn Val Gln 275 280 285 Ser Lys Cys Gly Ser Lys Asp Asn Ile Lys His Val Pro Gly Gly Gly 290 295 300 Ser Val Gln Ile Val Tyr Lys Pro Val Asp Leu Ser Lys Val Thr Ser 305 310 315 320 Lys Cys Gly Ser Leu Gly Asn Ile His His Lys Pro Gly Gly Gly Gln 325 330 335 Val Glu Val Lys Ser Glu Lys Leu Asp Phe Lys Asp Arg Val Gln Ser 340 345 350 Lys Ile Gly Ser Leu Asp Asn Ile Thr His Val Pro Gly Gly Gly Asn 355 360 365 Lys Lys Ile Glu Thr His Lys Leu Thr Phe Arg Glu Asn Ala Lys Ala 370 375 380 Lys Thr Asp His Gly Ala Glu Ile Val Tyr Lys Ser Pro Val Val Ser 385 390 395 400 Gly Asp Thr Ser Pro Arg His Leu Ser Asn Val Ser Ser Thr Gly Ser 405 410 415 Ile Asp Met Val Asp Ser Pro Gln Leu Ala Thr Leu Ala Asp Glu Val 420 425 430 Ser Ala Ser Leu Ala Lys Gln Gly Leu 435 440 3383PRTHomo sapiens 3Met Ala Glu Pro Arg Gln Glu Phe Glu Val Met Glu Asp His Ala Gly 1 5 10 15 Thr Tyr Gly Leu Gly Asp Arg Lys Asp Gln Gly Gly Tyr Thr Met His 20 25 30 Gln Asp Gln Glu Gly Asp Thr Asp Ala Gly Leu Lys Ala Glu Glu Ala 35 40 45 Gly Ile Gly Asp Thr Pro Ser Leu Glu Asp Glu Ala Ala Gly His Val 50 55 60 Thr Gln Ala Arg Met Val Ser Lys Ser Lys Asp Gly Thr Gly Ser Asp 65 70 75 80 Asp Lys Lys Ala Lys Gly Ala Asp Gly Lys Thr Lys Ile Ala Thr Pro 85 90 95 Arg Gly Ala Ala Pro Pro Gly Gln Lys Gly Gln Ala Asn Ala Thr Arg 100 105 110 Ile Pro Ala Lys Thr Pro Pro Ala Pro Lys Thr Pro Pro Ser Ser Gly 115 120 125 Glu Pro Pro Lys Ser Gly Asp Arg Ser Gly Tyr Ser Ser Pro Gly Ser 130 135 140 Pro Gly Thr Pro Gly Ser Arg Ser Arg Thr Pro Ser Leu Pro Thr Pro 145 150 155 160 Pro Thr Arg Glu Pro Lys Lys Val Ala Val Val Arg Thr Pro Pro Lys 165 170 175 Ser Pro Ser Ser Ala Lys Ser Arg Leu Gln Thr Ala Pro Val Pro Met 180 185 190 Pro Asp Leu Lys Asn Val Lys Ser Lys Ile Gly Ser Thr Glu Asn Leu 195 200 205 Lys His Gln Pro Gly Gly Gly Lys Val Gln Ile Ile Asn Lys Lys Leu 210 215 220 Asp Leu Ser Asn Val Gln Ser Lys Cys Gly Ser Lys Asp Asn Ile Lys 225 230 235 240 His Val Pro Gly Gly Gly Ser Val Gln Ile Val Tyr Lys Pro Val Asp 245 250 255 Leu Ser Lys Val Thr Ser Lys Cys Gly Ser Leu Gly Asn Ile His His 260 265 270 Lys Pro Gly Gly Gly Gln Val Glu Val Lys Ser Glu Lys Leu Asp Phe 275 280 285 Lys Asp Arg Val Gln Ser Lys Ile Gly Ser Leu Asp Asn Ile Thr His 290 295 300 Val Pro Gly Gly Gly Asn Lys Lys Ile Glu Thr His Lys Leu Thr Phe 305 310 315 320 Arg Glu Asn Ala Lys Ala Lys Thr Asp His Gly Ala Glu Ile Val Tyr 325 330 335 Lys Ser Pro Val Val Ser Gly Asp Thr Ser Pro Arg His Leu Ser Asn 340 345 350 Val Ser Ser Thr Gly Ser Ile Asp Met Val Asp Ser Pro Gln Leu Ala 355 360 365 Thr Leu Ala Asp Glu Val Ser Ala Ser Leu Ala Lys Gln Gly Leu 370 375 380 4758PRTHomo sapiens 4Met Ala Glu Pro Arg Gln Glu Phe Glu Val Met Glu Asp His Ala Gly 1 5 10 15 Thr Tyr Gly Leu Gly Asp Arg Lys Asp Gln Gly Gly Tyr Thr Met His 20 25 30 Gln Asp Gln Glu Gly Asp Thr Asp Ala Gly Leu Lys Glu Ser Pro Leu 35 40 45 Gln Thr Pro Thr Glu Asp Gly Ser Glu Glu Pro Gly Ser Glu Thr Ser 50 55 60 Asp Ala Lys Ser Thr Pro Thr Ala Glu Asp Val Thr Ala Pro Leu Val 65 70 75 80 Asp Glu Gly Ala Pro Gly Lys Gln Ala Ala Ala Gln Pro His Thr Glu 85 90 95 Ile Pro Glu Gly Thr Thr Ala Glu Glu Ala Gly Ile Gly Asp Thr Pro 100 105 110 Ser Leu Glu Asp Glu Ala Ala Gly His Val Thr Gln Glu Pro Glu Ser 115 120 125 Gly Lys Val Val Gln Glu Gly Phe Leu Arg Glu Pro Gly Pro Pro Gly 130 135 140 Leu Ser His Gln Leu Met Ser Gly Met Pro Gly Ala Pro Leu Leu Pro 145 150 155 160 Glu Gly Pro Arg Glu Ala Thr Arg Gln Pro Ser Gly Thr Gly Pro Glu 165 170 175 Asp Thr Glu Gly Gly Arg His Ala Pro Glu Leu Leu Lys His Gln Leu 180 185 190 Leu Gly Asp Leu His Gln Glu Gly Pro Pro Leu Lys Gly Ala Gly Gly 195 200 205 Lys Glu Arg Pro Gly Ser Lys Glu Glu Val Asp Glu Asp Arg Asp Val 210 215 220 Asp Glu Ser Ser Pro Gln Asp Ser Pro Pro Ser Lys Ala Ser Pro Ala 225 230 235 240 Gln Asp Gly Arg Pro Pro Gln Thr Ala Ala Arg Glu Ala Thr Ser Ile 245 250 255 Pro Gly Phe Pro Ala Glu Gly Ala Ile Pro Leu Pro Val Asp Phe Leu 260 265 270 Ser Lys Val Ser Thr Glu Ile Pro Ala Ser Glu Pro Asp Gly Pro Ser 275 280 285 Val Gly Arg Ala Lys Gly Gln Asp Ala Pro Leu Glu Phe Thr Phe His 290 295 300 Val Glu Ile Thr Pro Asn Val Gln Lys Glu Gln Ala His Ser Glu Glu 305 310 315 320 His Leu Gly Arg Ala Ala Phe Pro Gly Ala Pro Gly Glu Gly Pro Glu 325 330 335 Ala Arg Gly Pro Ser Leu Gly Glu Asp Thr Lys Glu Ala Asp Leu Pro 340 345 350 Glu Pro Ser Glu Lys Gln Pro Ala Ala Ala Pro Arg Gly Lys Pro Val 355 360 365 Ser Arg Val Pro Gln Leu Lys Ala Arg Met Val Ser Lys Ser Lys Asp 370 375 380 Gly Thr Gly Ser Asp Asp Lys Lys Ala Lys Thr Ser Thr Arg Ser Ser 385 390 395 400 Ala Lys Thr Leu Lys Asn Arg Pro Cys Leu Ser Pro Lys His Pro Thr 405 410 415 Pro Gly Ser Ser Asp Pro Leu Ile Gln Pro Ser Ser Pro Ala Val Cys 420 425 430 Pro Glu Pro Pro Ser Ser Pro Lys Tyr Val Ser Ser Val Thr Ser Arg 435 440 445 Thr Gly Ser Ser Gly Ala Lys Glu Met Lys Leu Lys Gly Ala Asp Gly 450 455 460 Lys Thr Lys Ile Ala Thr Pro Arg Gly Ala Ala Pro Pro Gly Gln Lys 465 470 475 480 Gly Gln Ala Asn Ala Thr Arg Ile Pro Ala Lys Thr Pro Pro Ala Pro 485 490 495 Lys Thr Pro Pro Ser Ser Gly Glu Pro Pro Lys Ser Gly Asp Arg Ser 500 505 510 Gly Tyr Ser Ser Pro Gly Ser Pro Gly Thr Pro Gly Ser Arg Ser Arg 515 520 525 Thr Pro Ser Leu Pro Thr Pro Pro Thr Arg Glu Pro Lys Lys Val Ala 530 535 540 Val Val Arg Thr Pro Pro Lys Ser Pro Ser Ser Ala Lys Ser Arg Leu 545 550 555 560 Gln Thr Ala Pro Val Pro Met Pro Asp Leu Lys Asn Val Lys Ser Lys 565 570 575 Ile Gly Ser Thr Glu Asn Leu Lys His Gln Pro Gly Gly Gly Lys Val 580 585 590 Gln Ile Ile Asn Lys Lys Leu Asp Leu Ser Asn Val Gln Ser Lys Cys 595 600 605 Gly Ser Lys Asp Asn Ile Lys His Val Pro Gly Gly Gly Ser Val Gln 610 615 620 Ile Val Tyr Lys Pro Val Asp Leu Ser Lys Val Thr Ser Lys Cys Gly 625 630 635 640 Ser Leu Gly Asn Ile His His Lys Pro Gly Gly Gly Gln Val Glu Val 645 650 655 Lys Ser Glu Lys Leu Asp Phe Lys Asp Arg Val Gln Ser Lys Ile Gly 660 665 670 Ser Leu Asp Asn Ile Thr His Val Pro Gly Gly Gly Asn Lys Lys Ile 675 680 685 Glu Thr His Lys Leu Thr Phe Arg Glu Asn Ala Lys Ala Lys Thr Asp 690 695 700 His Gly Ala Glu Ile Val Tyr Lys Ser Pro Val Val Ser Gly Asp Thr 705 710 715 720 Ser Pro Arg His Leu Ser Asn Val Ser Ser Thr Gly Ser Ile Asp Met 725 730 735 Val Asp Ser Pro Gln Leu Ala Thr Leu Ala Asp Glu Val Ser Ala Ser 740 745 750 Leu Ala Lys Gln Gly Leu 755 5776PRTHomo sapiens 5Met Ala Glu Pro Arg Gln Glu Phe Glu Val Met Glu Asp His Ala Gly 1 5 10 15 Thr Tyr Gly Leu Gly Asp Arg Lys Asp Gln Gly Gly Tyr Thr Met His 20 25 30 Gln Asp Gln Glu Gly Asp Thr Asp Ala Gly Leu Lys Glu Ser Pro Leu 35 40 45 Gln Thr Pro Thr Glu Asp Gly Ser Glu Glu Pro Gly Ser Glu Thr Ser 50 55 60 Asp Ala Lys Ser Thr Pro Thr Ala Glu Asp Val Thr Ala Pro Leu Val 65 70 75 80 Asp Glu Gly Ala Pro Gly Lys Gln Ala Ala Ala Gln Pro His Thr Glu 85 90 95 Ile Pro Glu Gly Thr Thr Ala Glu Glu Ala Gly Ile Gly Asp Thr Pro 100 105 110 Ser Leu Glu Asp Glu Ala Ala Gly His Val Thr Gln Glu Pro Glu Ser 115 120 125 Gly Lys Val Val Gln Glu Gly Phe Leu Arg Glu Pro Gly Pro Pro Gly 130 135 140 Leu Ser His Gln Leu Met Ser Gly Met Pro Gly Ala Pro Leu Leu Pro 145 150 155 160 Glu Gly Pro Arg Glu Ala Thr Arg Gln Pro Ser Gly Thr Gly Pro Glu 165 170 175 Asp Thr Glu Gly Gly Arg His Ala Pro Glu Leu Leu Lys His Gln Leu 180 185 190 Leu Gly Asp Leu His Gln Glu Gly Pro Pro Leu Lys Gly Ala Gly Gly 195 200 205 Lys Glu Arg Pro Gly Ser Lys Glu Glu Val Asp Glu Asp Arg Asp Val 210 215 220 Asp Glu Ser Ser Pro Gln Asp Ser Pro Pro Ser Lys Ala Ser Pro Ala 225 230 235 240 Gln Asp Gly Arg Pro Pro Gln Thr Ala Ala Arg Glu Ala Thr Ser Ile 245 250 255 Pro Gly Phe Pro Ala Glu Gly Ala Ile Pro Leu Pro Val Asp Phe Leu 260 265 270 Ser Lys Val Ser Thr Glu Ile Pro Ala Ser Glu Pro Asp Gly Pro Ser 275 280 285 Val Gly Arg Ala Lys Gly Gln Asp Ala Pro Leu Glu Phe Thr Phe His 290 295 300 Val Glu Ile Thr Pro Asn Val Gln Lys Glu Gln Ala His Ser Glu Glu 305 310 315 320 His Leu Gly Arg Ala Ala Phe Pro Gly Ala Pro Gly Glu Gly Pro Glu 325 330 335 Ala Arg Gly Pro Ser Leu Gly Glu Asp Thr Lys Glu Ala Asp Leu Pro 340 345 350 Glu Pro Ser Glu Lys Gln Pro Ala Ala Ala Pro Arg Gly Lys

Pro Val 355 360 365 Ser Arg Val Pro Gln Leu Lys Ala Arg Met Val Ser Lys Ser Lys Asp 370 375 380 Gly Thr Gly Ser Asp Asp Lys Lys Ala Lys Thr Ser Thr Arg Ser Ser 385 390 395 400 Ala Lys Thr Leu Lys Asn Arg Pro Cys Leu Ser Pro Lys His Pro Thr 405 410 415 Pro Gly Ser Ser Asp Pro Leu Ile Gln Pro Ser Ser Pro Ala Val Cys 420 425 430 Pro Glu Pro Pro Ser Ser Pro Lys Tyr Val Ser Ser Val Thr Ser Arg 435 440 445 Thr Gly Ser Ser Gly Ala Lys Glu Met Lys Leu Lys Gly Ala Asp Gly 450 455 460 Lys Thr Lys Ile Ala Thr Pro Arg Gly Ala Ala Pro Pro Gly Gln Lys 465 470 475 480 Gly Gln Ala Asn Ala Thr Arg Ile Pro Ala Lys Thr Pro Pro Ala Pro 485 490 495 Lys Thr Pro Pro Ser Ser Ala Thr Lys Gln Val Gln Arg Arg Pro Pro 500 505 510 Pro Ala Gly Pro Arg Ser Glu Arg Gly Glu Pro Pro Lys Ser Gly Asp 515 520 525 Arg Ser Gly Tyr Ser Ser Pro Gly Ser Pro Gly Thr Pro Gly Ser Arg 530 535 540 Ser Arg Thr Pro Ser Leu Pro Thr Pro Pro Thr Arg Glu Pro Lys Lys 545 550 555 560 Val Ala Val Val Arg Thr Pro Pro Lys Ser Pro Ser Ser Ala Lys Ser 565 570 575 Arg Leu Gln Thr Ala Pro Val Pro Met Pro Asp Leu Lys Asn Val Lys 580 585 590 Ser Lys Ile Gly Ser Thr Glu Asn Leu Lys His Gln Pro Gly Gly Gly 595 600 605 Lys Val Gln Ile Ile Asn Lys Lys Leu Asp Leu Ser Asn Val Gln Ser 610 615 620 Lys Cys Gly Ser Lys Asp Asn Ile Lys His Val Pro Gly Gly Gly Ser 625 630 635 640 Val Gln Ile Val Tyr Lys Pro Val Asp Leu Ser Lys Val Thr Ser Lys 645 650 655 Cys Gly Ser Leu Gly Asn Ile His His Lys Pro Gly Gly Gly Gln Val 660 665 670 Glu Val Lys Ser Glu Lys Leu Asp Phe Lys Asp Arg Val Gln Ser Lys 675 680 685 Ile Gly Ser Leu Asp Asn Ile Thr His Val Pro Gly Gly Gly Asn Lys 690 695 700 Lys Ile Glu Thr His Lys Leu Thr Phe Arg Glu Asn Ala Lys Ala Lys 705 710 715 720 Thr Asp His Gly Ala Glu Ile Val Tyr Lys Ser Pro Val Val Ser Gly 725 730 735 Asp Thr Ser Pro Arg His Leu Ser Asn Val Ser Ser Thr Gly Ser Ile 740 745 750 Asp Met Val Asp Ser Pro Gln Leu Ala Thr Leu Ala Asp Glu Val Ser 755 760 765 Ala Ser Leu Ala Lys Gln Gly Leu 770 775 6412PRTHomo sapiens 6Met Ala Glu Pro Arg Gln Glu Phe Glu Val Met Glu Asp His Ala Gly 1 5 10 15 Thr Tyr Gly Leu Gly Asp Arg Lys Asp Gln Gly Gly Tyr Thr Met His 20 25 30 Gln Asp Gln Glu Gly Asp Thr Asp Ala Gly Leu Lys Glu Ser Pro Leu 35 40 45 Gln Thr Pro Thr Glu Asp Gly Ser Glu Glu Pro Gly Ser Glu Thr Ser 50 55 60 Asp Ala Lys Ser Thr Pro Thr Ala Glu Ala Glu Glu Ala Gly Ile Gly 65 70 75 80 Asp Thr Pro Ser Leu Glu Asp Glu Ala Ala Gly His Val Thr Gln Ala 85 90 95 Arg Met Val Ser Lys Ser Lys Asp Gly Thr Gly Ser Asp Asp Lys Lys 100 105 110 Ala Lys Gly Ala Asp Gly Lys Thr Lys Ile Ala Thr Pro Arg Gly Ala 115 120 125 Ala Pro Pro Gly Gln Lys Gly Gln Ala Asn Ala Thr Arg Ile Pro Ala 130 135 140 Lys Thr Pro Pro Ala Pro Lys Thr Pro Pro Ser Ser Gly Glu Pro Pro 145 150 155 160 Lys Ser Gly Asp Arg Ser Gly Tyr Ser Ser Pro Gly Ser Pro Gly Thr 165 170 175 Pro Gly Ser Arg Ser Arg Thr Pro Ser Leu Pro Thr Pro Pro Thr Arg 180 185 190 Glu Pro Lys Lys Val Ala Val Val Arg Thr Pro Pro Lys Ser Pro Ser 195 200 205 Ser Ala Lys Ser Arg Leu Gln Thr Ala Pro Val Pro Met Pro Asp Leu 210 215 220 Lys Asn Val Lys Ser Lys Ile Gly Ser Thr Glu Asn Leu Lys His Gln 225 230 235 240 Pro Gly Gly Gly Lys Val Gln Ile Ile Asn Lys Lys Leu Asp Leu Ser 245 250 255 Asn Val Gln Ser Lys Cys Gly Ser Lys Asp Asn Ile Lys His Val Pro 260 265 270 Gly Gly Gly Ser Val Gln Ile Val Tyr Lys Pro Val Asp Leu Ser Lys 275 280 285 Val Thr Ser Lys Cys Gly Ser Leu Gly Asn Ile His His Lys Pro Gly 290 295 300 Gly Gly Gln Val Glu Val Lys Ser Glu Lys Leu Asp Phe Lys Asp Arg 305 310 315 320 Val Gln Ser Lys Ile Gly Ser Leu Asp Asn Ile Thr His Val Pro Gly 325 330 335 Gly Gly Asn Lys Lys Ile Glu Thr His Lys Leu Thr Phe Arg Glu Asn 340 345 350 Ala Lys Ala Lys Thr Asp His Gly Ala Glu Ile Val Tyr Lys Ser Pro 355 360 365 Val Val Ser Gly Asp Thr Ser Pro Arg His Leu Ser Asn Val Ser Ser 370 375 380 Thr Gly Ser Ile Asp Met Val Asp Ser Pro Gln Leu Ala Thr Leu Ala 385 390 395 400 Asp Glu Val Ser Ala Ser Leu Ala Lys Gln Gly Leu 405 410

Claims

1. A method of reducing intracellular tau phosphorylation levels, wherein the method comprises administering, to cells comprising phosphorylated protein tau, an effective amount of compound B: ##STR00010##

2. The method according to claim 1, wherein the cells are in a subject in need of treatment for a neurodegenerative disease.

3. The method of claim 2, wherein the neurodegenerative disease is a tauopathy.

4. The method of claim 3, wherein the subject is a human.

5. The method of claim 4, wherein the neurodegenerative disease is selected from Alzheimer's disease, Parkinson's disease, frontotemporal dementia, frontotemporal dementia with Parkinsonism, frontotemporal lobe dementia, pallidopontonigral degeneration, progressive supranuclear palsy, multiple system tauopathy, multiple system tauopathy with presenile dementia, Wilhelmsen-Lynch disease, Pick's disease, or Pick's disease-like dementia.

6. The method of claim 4, wherein the neurodegenerative disease is Alzheimer's disease.

7. A pharmaceutical composition comprising a therapeutically effective amount of a compound selected from compound A ##STR00011## compound B ##STR00012## and combinations thereof; and a pharmaceutically acceptable carrier or adjuvant.