This proposal outlines the development of new chemical methods for alkyl-alkyl cross-coupling reactions to form carbon-carbon bonds and application of these methods for synthesis of lead compounds that will be evaluated for anti-cancer activity. The objectives of this project are to generate new strategies for stereospecific cross-coupling reactions, where the stereochemical information from the electrophilic reaction partner is translated to the newly formed stereogenic center of the product. These methods will be utilized in the synthesis of di- and triarylmethane analogs of anti-cancer agents. Collaborative studies to test the activity of these analogues for inhibition of tubulin polymerization, as well a broad screens against several cancer cell lines, will also be performed. This project will directly impact the development of new pharmaceutical agents by providing new strategies for their preparation and validation of the therapeutic potential of the enantioenriched diarylmethane pharmacophore.

Public Health Relevance

The development of new chemical methods for organic synthesis is essential in the preparation of natural products and other bioactive molecules for preliminary biological studies, clinical trials, and production for market. Despite the advanced state of synthetic chemistry, serious challenges remain for forming di- and triarylmethanes enantioselectively. This proposal addresses two main goals: 1) development of new cross-coupling reactions that form tertiary stereogenic centers with control of absolute stereochemistry, and 2) biological testing of these di- and triarylmethane libraries as lead compounds for anti-cancer agents, through their evaluation against microtubule polymerization and cancer cell lines.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31CA177212-01
Application #
8527576
Study Section
Special Emphasis Panel (ZRG1-F04-W (20))
Program Officer
Damico, Mark W
Project Start
2013-04-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$35,622
Indirect Cost
Name
University of California Irvine
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
046705849
City
Irvine
State
CA
Country
United States
Zip Code
92697
Yonova, Ivelina M; Osborne, Charlotte A; Morrissette, Naomi S et al. (2014) Diaryl and heteroaryl sulfides: synthesis via sulfenyl chlorides and evaluation as selective anti-breast-cancer agents. J Org Chem 79:1947-53
Yonova, Ivelina M; Johnson, A George; Osborne, Charlotte A et al. (2014) Stereospecific nickel-catalyzed cross-coupling reactions of alkyl Grignard reagents and identification of selective anti-breast-cancer agents. Angew Chem Int Ed Engl 53:2422-7
Tollefson, Emily J; Dawson, David D; Osborne, Charlotte A et al. (2014) Stereospecific cross-coupling reactions of aryl-substituted tetrahydrofurans, tetrahydropyrans, and lactones. J Am Chem Soc 136:14951-8