Discovery of (E)-9,10-Dehydroepothilones through Chemical Synthesis: On the Emergence of 26-Trifluoro-(E)-9,10-dehydro-12,13-desoxyepothilone B as a Promising Anticancer Drug Cand
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- 作者：Alexey Rivkin ; Fumihiko Yoshimura ; Ana E. Gabarda ; Young Shin Cho ; Ting-Chao Chou ; Huajin Dong ; and Samuel J. Danishefsky
- 刊名：Journal of the American Chemical Society
- 出版年：2004
- 出版时间：September 8, 2004
- 年：2004
- 卷：126
- 期：35
- 页码：10913 - 10922
- 全文大小：438K
- 年卷期：v.126,no.35(September 8, 2004)
- ISSN：1520-5126
文摘
We provide a full account of the discovery of the (E)-9,10-dehydro derivatives of 12,13-desoxyepothilone B (dEpoB), a new class of antitumor agents with promising in vivo preclinical properties.The compounds, which are to date not available by modification of any of the naturally occurring epothilones,were discovered through total chemical synthesis. We describe how our investigations of ring-closingmetathesis reactions in epothilone settings led to the first and second generation syntheses of (E)-9,10-dehydro-12,13-desoxyepothilone congener 6. With further modifications, the synthesis was applied to reacha 26-trifluoro derivative compound (see compound 7). To conduct such studies and in anticipation of futuredevelopment needs, the total synthesis which led to the initial discovery of compound 7 was simplifiedsignificantly. The total synthesis methodology used to reach compound 7 was then applied to reach morereadily formulated compounds, bearing hydroxy and amino functionality on the 21-position (see compounds45, 62, and 63). Following extensive in vitro evaluations of these new congeners, compound 7 was nominatedfor in vivo evaluations in xenograft models. The data provided herein demonstrate a promising therapeuticefficacy, activity against large tumors, nonrelapseability, and oral activity. These results have identifiedcompound 7 as a particularly promising compound for clinical development. The excellent, totally synthetic,route to 7 makes such a program quite feasible.