Design and synthesis of ring-fused and conformationally restrained epothilone analogs

MEDI 58

Weiqiang Zhan, wzhan@emory.edu1, Yi Jiang, yjiang4@emory.edu1, Susan Bane2, Abhijit Banerjee3, Dennis C. Liotta1, and James P. Snyder, jsnyder@emory.edu1. (1) Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, GA 30322, (2) Department of Chemistry, State University of New York, Binghamton, NY 13902-6016, (3) Department of Chemistry, State University of New York at Binghamton, Binghamton, NY 13902
Epothilones A and B are polyketide macrolides originally isolated from myxobactria. The compounds are potent cytotoxins against a wide variety of cancer cells, exert their action by stabilizing microtubules, and associate with beta-tubulin at the binding site utilized by Taxol. The exceptional anti-cancer characteristics of epothilones, combined with their improved resistance profile and ease of synthesis by comparison with Taxol, has resulted in several ongoing clinical trials evaluating the anti-tumor potential of the compound class. Recently, our group proposed a unique epothilone A conformation and microtubule binding model based on electron crystallography, ligand conformer deconvolution by NMR and SAR analysis[1]. To test geometric details of the epothilone conformation in the C-4~C-8 sector, we applied molecular modeling and protein-ligand docking to the design of a series of conformationally restrained epothilone analogues incorporating a short bridge between the methyl groups at C-4 and C-6 or C-6 and C-8. The rationale for the design, stereochemical implications, approaches to the synthesis of the fused-ring epothilone analogues and biological results will be presented.

[1] Nettles, J. H.; Li, H.; Cornett, B.; Krahn, J. M.; Snyder, J. P.; Downing, K. H. Science 2004, 305, 866-869.

 

General Poster Session
7:00 PM-9:00 PM, Sunday, 10 September 2006 Moscone Center -- Hall D, Poster

Division of Medicinal Chemistry

The 232nd ACS National Meeting, San Francisco, CA, September 10-14, 2006