Misfolded, amyloid-like protein deposits in cells and tissues are commonly associated with numerous human diseases, including Alzheimer's disease (AD), prion diseases, Parkinson's disease, Type-II diabetes etc. representing tremendous medical, social and financial problems. The Alzheimer's disease involves the formation of extracellular fibrillar deposits of amyloid-beta (A2) peptide known as amyloid plaques (senile plaques). These fibrils (polymeric aggregates) and soluble oligomers of A2 peptide are associated with pathology. Accordingly, the inhibition of both seeding and self-assembly process of A2 is a promising therapeutic strategy. The principal goal of this proposal is to develop effective inhibitor compounds against the self-assembly of A2. As a continuation of our ongoing studies, we propose the synthesis of a broad variety of new compounds based on a core structure designed earlier. Our investigations have resulted in the identification of lead compounds and have also provided some indication of possible binding mechanism between the peptide and the inhibitors. In this proposal these prior results will be expanded upon and further work is proposed to perform a systematic synthetic study to create a large number of derivatives of the lead compounds. We will study the effect of these new inhibitor candidates on the self-assembly of the A2 peptide, including the formation of oligomers and fibrils. We intend to develop a broad structure-activity relationship scheme using a large set of structurally similar compounds. In a recent study we have observed that while the large number of reported inhibitors contain common structural motifs, these compounds are structurally diverse. It is our hypothesis that using a broad variety of inhibitors based on the same core structure we will describe a SAR that will be useful in classifying the crucial structural elements that an effective inhibitor should possess. We will test this hypothesis in this proposal with the ultimate goal to identify new effective inhibitors for A2 self- assembly.

Public Health Relevance

Misfolded, amyloid-like protein deposits in cells and tissues are commonly associated with numerous human diseases, including Alzheimer's disease (AD). The principal goal of this proposal is to develop effective inhibitor compounds against the self-assembly of Alzheimer's amyloid beta peptide and contribute to the discovery of novel drug candidates against Alzheimer's disease and related amyloid disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Academic Research Enhancement Awards (AREA) (R15)
Project #
2R15AG025777-03A1
Application #
7779007
Study Section
Biophysics of Neural Systems Study Section (BPNS)
Program Officer
Buckholtz, Neil
Project Start
2005-05-15
Project End
2012-08-31
Budget Start
2009-09-30
Budget End
2012-08-31
Support Year
3
Fiscal Year
2009
Total Cost
$201,300
Indirect Cost
Name
University of Massachusetts Boston
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
808008122
City
Boston
State
MA
Country
United States
Zip Code
02125
Bag, Seema; Ghosh, Sanjukta; Tulsan, Rekha et al. (2013) Design, synthesis and biological activity of multifunctional ?,?-unsaturated carbonyl scaffolds for Alzheimer's disease. Bioorg Med Chem Lett 23:2614-8
Török, Béla; Sood, Abha; Bag, Seema et al. (2013) Diaryl hydrazones as multifunctional inhibitors of amyloid self-assembly. Biochemistry 52:1137-48
Cho, Hyejin; Torok, Fanni; Torok, Bela (2013) Selective reduction of condensed N-heterocycles using water as a solvent and a hydrogen source. Org Biomol Chem 11:1209-15
Bag, Seema; Tulsan, Rekha; Sood, Abha et al. (2013) Pharmacophore Modeling, virtual and in vitro screening for acetylcholinesterase inhibitors and their effects on amyloid-? self- assembly. Curr Comput Aided Drug Des 9:2-14
Török, Béla; Sood, Abha; Bag, Seema et al. (2012) Structure-activity relationships of organofluorine inhibitors of ?-amyloid self-assembly. ChemMedChem 7:910-9
Borkin, Dmitry; Morzhina, Elena; Datta, Silpi et al. (2011) Heteropoly acid-catalyzed microwave-assisted three-component aza-Diels-Alder cyclizations: diastereoselective synthesis of potential drug candidates for Alzheimer's disease. Org Biomol Chem 9:1394-401
Borkin, Dmitry A; Landge, Shainaz M; Torok, Bela (2011) Enantioselective Friedel-Crafts reaction of indoles with trifluoroacetaldehyde catalyzed by Cinchona alkaloids. Chirality 23:612-6
Sood, Abha; Abid, Mohammed; Sauer, Catharine et al. (2011) Disassembly of preformed amyloid beta fibrils by small organofluorine molecules. Bioorg Med Chem Lett 21:2044-7
Kulkarni, Aditya; Zhou, Weihong; Torok, Bela (2011) Heterogeneous catalytic hydrogenation of unprotected indoles in water: a green solution to a long-standing challenge. Org Lett 13:5124-7
Sood, Abha; Abid, Mohammed; Hailemichael, Samson et al. (2009) Effect of chirality of small molecule organofluorine inhibitors of amyloid self-assembly on inhibitor potency. Bioorg Med Chem Lett 19:6931-4

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