Synthesis, structure proof, and biological activity of epothilone cyclopropanes.
[structure--see text] A semisynthetic route to epothilone cyclopropanes from epothilones A and B is described. Of significance, the deoxygenation of the 12, 13-epoxide to give the corresponding olefin was achieved with high efficiency. The title compounds (8, 9) were active in both tubulin polymerization and cytotoxicity assays, which is in direct contrast to a previously published report. These results provide further evidence that the role of the 12,13-epoxide of epothilones is largely conformational and argue against some of the current pharmacophore models.
Johnson
J
J
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000, USA.
Kim
S H
SH
Bifano
M
M
DiMarco
J
J
Fairchild
C
C
Gougoutas
J
J
Lee
F
F
Long
B
B
Tokarski
J
J
Vite
G
G
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D034261:Epothilones; D004852:Epoxy Compounds / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D013816:Thermodynamics; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; C113666:C12,13-cyclopropylepothilone A; D034261:Epothilones; D004852:Epoxy Compounds; D007783:Lactones; D013844:Thiazoles; D014404:Tubulin; C093787:epothilone A; C093788:epothilone B