Molecular libraries derived from an imidazole-4,5-dicarboxylic acid (I45DA) scaffold are proposed. Multiple classes of compounds are targeted, including monomeric and oligomeric I45DA derivatives. The nearly 1200 monomeric I45DA derivatives have structural and conformational features necessary to interact with receptors, kinases, ion channels, enzymes, and cytoskeletal proteins. Two partially overlapping subsets of these compounds have either a free amine or carboxylic acid that can be used for derivatization with probes. All of the compounds can be modified through the imidazole ring. Symmetrical oligomeric I45DA derivatives bearing anilines can interfere with the same protein targets as above, as well as with unique targets like receptor dimers. A class of linear I45DA oligomers prepared with amino acid substituents and approximating 500 members is designed to discover inhibitors of protein-protein interactions. These compounds can be derivatized with probes at either free amine or carboxylic acid functionalities. Thus, our specific aims are summarized as follows: 1) to deliver 719 monomeric I45DA derivatives that include diamides, ester-amide, and diester combinations, 2) to deliver analogs of the first specific aim modified by imidazole ring alkylation, functional group derivitization around a bioactive lead, and by removing protecting groups to yield 322 compounds amenable to probe derivitization, and 3) to deliver approximately 500 oligomeric I45DA derivatives, the majority of which bear amino acid side chains for inhibiting protein-protein interactions. We will prepare the I45DA libraries in small, parallel syntheses. All compounds will be characterized for identity by hydrogen NMR and LC-MS analysis with detection at 214 nm. ? ? Small molecule tools for studying the cell and cellular processes promise to improve our understanding of disease development and progression. The I45DA derivatives are easy to prepare and the compounds, as well as the synthetic methodology to make them, will be made public. This will provide a valuable set of resources for biomedical researchers and to those interested in developing new clinical therapeutics based on the structure-activity relationships of these compounds. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Biotechnology Resource Grants (P41)
Project #
5P41GM079589-03
Application #
7484158
Study Section
Special Emphasis Panel (ZGM1-PPBC-3 (PL))
Program Officer
Schwab, John M
Project Start
2006-09-15
Project End
2010-08-31
Budget Start
2008-09-01
Budget End
2010-08-31
Support Year
3
Fiscal Year
2008
Total Cost
$156,507
Indirect Cost
Name
University of Tulsa
Department
Chemistry
Type
Schools of Engineering
DUNS #
072420433
City
Tulsa
State
OK
Country
United States
Zip Code
74104
Xu, Zhigang; Wheeler, Kraig A; Baures, Paul W (2012) Parallel synthesis of peptide-like macrocycles containing imidazole-4,5-dicarboxylic acid. Molecules 17:5346-62
Baures, Paul W (2012) Is ROR? a therapeutic target for treating Mycobacterium tuberculosis infections? Tuberculosis (Edinb) 92:95-9
Xu, Zhigang; DiCesare, John C; Baures, Paul W (2010) Parallel synthesis of an oligomeric imidazole-4,5-dicarboxamide library. J Comb Chem 12:248-54
Solinas, Rosanna; DiCesare, John C; Baures, Paul W (2009) Parallel synthesis of a library of symmetrically- and dissymmetrically-disubstituted imidazole-4,5-dicarboxamides bearing amino acid esters. Molecules 14:352-63
Solinas, Rosanna; DiCesare, John C; Baures, Paul W (2008) Parallel synthesis of an imidazole-4,5-dicarboxamide library bearing amino acid esters and alkanamines. Molecules 13:3149-70