Total synthesis and antitumor activity of 12,13-desoxyepothilone F: an unexpected solvolysis problem at C15, mediated by remote substitution at C21.
A new epothilone analogue, 12,13-desoxyepothilone F (dEpoF, 21-hydroxy-12,13-desoxyepothilone B, 21-hydroxyepothilone D), was synthesized and evaluated for antitumor potential. A convergent strategy employed for the semipractical synthesis of 12,13-desoxyepothilone B (dEpoB) has been utilized to yield an amount of dEpoF sufficient for relevant biological studies. The results from an in vitro assay reveal that this new analogue is highly active against various tumor cell lines with a potency comparable to that of dEpoB. In particular, the growth of resistant tumor cells is inhibited by dEpoF at concentrations where paclitaxel (Taxol) is basically ineffective. A preliminary assessment of its in vivo activity is also promising. The new analogue, containing an additional hydroxyl group at C21, exhibits advantages over other epothilones in terms of water solubility, and can serve as a readily functionalizable handle to produce other useful compounds for pertinent biological studies.
Lee
C B
CB
The Laboratory for Bioorganic Chemistry, The Sloan-Kettering Institute for Cancer Research, New York, New York 10021, USA.
Chou
T C
TC
Zhang
X G
XG
Wang
Z G
ZG
Kuduk
S D
SD
Chappell
M D
MD
Stachel
S J
SJ
Danishefsky
S J
SJ
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D004354:Drug Screening Assays, Antitumor; D034261:Epothilones; D006801:Humans; D007783:Lactones / Q000138:chemical synthesis* / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D017239:Paclitaxel / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
C416065:12,13-desoxyepothilone F; D000970:Antineoplastic Agents; D000972:Antineoplastic Agents, Phytogenic; D034261:Epothilones; D007783:Lactones; D013844:Thiazoles; D017239:Paclitaxel