具有强大体外抗肿瘤活性的超修饰埃坡霉素类似物的全合成。

Total synthesis of hypermodified epothilone analogs with potent in vitro antitumor activity.

作者信息

Kuzniewski Christian N, Gertsch Jürg, Wartmann Markus, Altmann Karl-Heinz

机构信息

Swiss Federal Institute of Technology (ETH) Zürich, HCI H405, Wolfgang-Pauli-Str. 10, CH-8093 Zürich, Switzerland.

出版信息

Org Lett. 2008 Mar 20;10(6):1183-6. doi: 10.1021/ol800089x. Epub 2008 Feb 28.

DOI:10.1021/ol800089x

PMID:18303900

Abstract

The convergent total synthesis of hypermodified epothilone analogs 1 and 2 has been achieved with the stereoselective cyclopropanation of allylic alcohol 17 and ring-closing olefin metathesis with diene 22 as the key steps. In spite of significant structural differences between these analogs and the natural epothilone scaffold, 1 and 2 are potent inducers of tubulin polymerization and inhibit the growth of human cancer cells in vitro with sub-nM IC50 values.

摘要

通过烯丙醇17的立体选择性环丙烷化反应以及与二烯22的闭环烯烃复分解反应作为关键步骤，实现了超修饰埃坡霉素类似物1和2的汇聚式全合成。尽管这些类似物与天然埃坡霉素骨架在结构上存在显著差异，但1和2仍是微管蛋白聚合的有效诱导剂，并且在体外以亚纳摩尔IC50值抑制人癌细胞的生长。