Highly Potent Triazole-Based Tubulin Polymerization Inhibitors
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- 作者：Qiang Zhang ; Youyi Peng ; Xin I. Wang ; Susan M. Keenan ; Sonia Arora ; William J. Welsh
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：February 22, 2007
- 年：2007
- 卷：50
- 期：4
- 页码：749 - 754
- 全文大小：197K
- 年卷期：v.50,no.4(February 22, 2007)
- ISSN：1520-4804
文摘
We describe the synthesis and biological evaluation of a series of tubulin polymerization inhibitors thatcontain the 1,2,4-triazole ring to retain the bioactive configuration afforded by the cis double bond incombretastatin A-4 (CA-4). Several of the subject compounds exhibited potent tubulin polymerizationinhibitory activity as well as cytotoxicity against a variety of cancer cells including multi-drug-resistant(MDR) cancer cell lines. Attachment of the N-methyl-5-indolyl moiety to the 1,2,4-triazole core, asexemplified by compound 7, conferred optimal properties among this series. Computer docking and molecularsimulations of 7 inside the colchicine binding site of tubulin enabled identification of residues most likelyto interact strongly with these inhibitors and explain their potent anti-tubulin activity and cytotoxicity. It ishoped that results presented here will stimulate further examination of these substituted 1,2,4-triazoles aspotential anti-cancer therapeutic agents.