Synthesis and biological properties of C12,13-cyclopropyl-epothilone A and related epothilones.
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.
Nicolaou
K C
KC
Department 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
Finlay
M R
MR
Ninkovic
S
S
King
N P
NP
He
Y
Y
Li
T
T
Sarabia
F
F
Vourloumis
D
D
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D034261:Epothilones; D007783:Lactones / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D014404:Tubulin / Q000187:drug effects; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; C113666:C12,13-cyclopropylepothilone A; D034261:Epothilones; D007783:Lactones; D013844:Thiazoles; D014404:Tubulin