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Synthesis and biological properties of C12,13-cyclopropyl-epothilone A and related epothilones
K C Nicolaou1, M R Finlay, S Ninkovic
1Department of Chemistry The Skaggs Institute for Chemical Biology The Scripps Research Institute 10550 North Torrey Pines Road, La Jolla, CA 92037, USA. kcn@scripps.edu
Background:
The epothilones are natural substances that are potently cytotoxic, having an almost identical mode of action to Taxoltrade mark as tubulin-polymerization and microtubule-stabilizing agents. The development of detailed structure-activity relationships for these compounds and the further elucidation of their mechanism of action is of high priority.
Results:
The chemical synthesis of the C12,13-cyclopropyl analog of epothilone A and its C12,13-trans-diastereoisomer has been accomplished. These compounds and several other epothilone analogs have been screened for their ability to induce tubulin polymerization and death of a number of tumor cells. Several interesting structure-activity trends within this family of compounds were identified.
Conclusions:
The results of the biological tests conducted in this study have demonstrated that, although a number of positions on the epothilone skeleton are amenable to modification without significant loss of biological activity, the replacement of the epoxide moiety of epothilone A with a cyclopropyl group leads to total loss of activity.