SYNTHESIS AND BIOLOGICAL PROPERTIES OF C12,13-CYCLOPROPYLEPOTHILONE AAND RELATED EPOTHILONES

Background: The epothilones are natural substances that are potently c ytotoxic, having an almost identical mode of action to Taxol(TM) as tu bulin-polymerization and microtubule-stabilizing agents. The developme nt of detailed structure-activity relationships for these compounds an d the further elucidation of their mechanism of action is of high prio rity. Results: The chemical synthesis of the C12,13-cyclopropyl analog of epothilone A and its C12,13-trans-diastereoisomer has been accompl ished. 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 tre nds within this family of compounds were identified. Conclusions: The results of the biological tests conducted in this study have demonstra ted that, although a number of positions on the epothilone skeleton ar e amenable to modification without significant loss of biological acti vity, the replacement of the epoxide moiety of epothilone A with a cyc lopropyl group leads to total loss of activity.