Restoration of Microtubule Interaction and Cytotoxicity in D-seco Taxanes upon Incorporation of 20-Hydroxymethyl-4-allyloxy Groups

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• 作者：Shao-Rong Wang ; Chun-Gang Yang ; Pedro A. S谩nchez-Murcia ; James P. Snyder ; Ning Yan ; Gonzalo S谩ez-Calvo ; Jos茅 Fernando D铆az ; Federico Gago ; Wei-Shuo Fang
• 刊名：Organic Letters
• 出版年：2015
• 出版时间：December 18, 2015
• 年：2015
• 卷：17
• 期：24
• 页码：6098-6101
• 全文大小：287K
• ISSN：1523-7052

文摘

To probe the exact role of the oxetane D ring in both tubulin binding and cytotoxicity of taxanes, novel D-seco taxanes bearing a C4 ether substituent have been prepared from paclitaxel 1a. Among them, 20-hydroxymethyl-4-allyloxy D-seco taxane 5e is the most active in both tubulin and cytotoxicity assays. It is only slightly less potent than 1a on tubulin polymerization promotion in vitro and the most cytotoxic among all D-seco taxanes known to date. The reason for the loss and restoration of bioactivity for these D-seco taxanes is also discussed with the assistance of NMR and molecular modeling studies. From these results, we draw a conclusion that the intact D ring of taxanes is not strictly necessary for their binding to tubulin and cytotoxic effects.