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J Med Chem. 2007 Mar 8;50(5):1001-6. Epub 2007 Feb 8.

Potent antitubulin tumor cell cytotoxins based on 3-aroyl indazoles.

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1
Threshold Pharmaceuticals, 1300 Seaport Boulevard, Redwood City, California 94063, USA. jduan@thresholdpharm.com

Abstract

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 [3H]colchicine and purified tubulins demonstrated that the compound specifically binds to the colchicine site.

PMID:
17286393
DOI:
10.1021/jm061348t
[Indexed for MEDLINE]
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