Complex Target-Oriented Total Synthesis in the Drug Discovery Process: The Discovery of a Highly Promising Family of Second Generation Epothilones

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• 作者：Alexey Rivkin ; Fumihiko Yoshimura ; Ana E. Gabarda ; Ting-Chao Chou ; Huajin Dong ; William P. Tong ; and Samuel J. Danishefsky
• 刊名：Journal of the American Chemical Society
• 出版年：2003
• 出版时间：March 12, 2003
• 年：2003
• 卷：125
• 期：10
• 页码：2899 - 2901
• 全文大小：69K
• 年卷期：v.125,no.10(March 12, 2003)
• ISSN：1520-5126

文摘

The total synthesis of a family of (E)-9,10-dehydro derivatives of epothilone D (i.e., 12,13-desoxyepothilone B) is described. The route is particularly concise and amenable to production of new congeners. Furthermore, the chemistry described herein constitutes a major simplification in the total synthesis of EpoD, which is in human clinical trials. This new family of epothilones shows major advantages in terms of their potency and pharmacostability relative to the wild-type saturated analogues in the D series. From the perspective of compound availability through synthesis, potency, and pharmacokinetic properties, these compounds could well warrant advancement to clinical evaluation in humans.