Potent antitubulin tumor cell cytotoxins based on 3-aroyl indazoles

被引：55

作者：

Duan, Jian-Xin ^{[1
]}

Cai, Xiaohong ^{[1
]}

Meng, Fanying ^{[1
]}

Lan, Leslie ^{[1
]}

Hart, Charles ^{[1
]}

Matteucci, Mark ^{[1
]}

机构：

[1] Threshold Pharmaceut, Redwood City, CA 94063 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2007年 / 50卷 / 05期

关键词：

D O I：

10.1021/jm061348t

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 3-aroyl indazoles was synthesized. Modification of the C-7 position resulted in a significant structure-activity relationship (SAR) with acetylene modifications conferring unusual potency in a tumor cell cytotoxicity assay. The most potent compounds exceeded the activity of combretastatin A4 (CA-4), showing single digit nM IC50 values against all cell lines tested including those with known efflux resistance pumps. The inhibition of in vitro tubulin polymerization was comparable to CA-4, consistent with tubulin being the target for these compounds. Competition binding experiments employing [H-3]colchicine and purified tubulins demonstrated that the compound specifically binds to the colchicine site.

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页码：1001 / 1006

页数：6

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