A-Ring Dihalogenation Increases the Cellular Activity of Combretastatin-Templated Tetrazoles

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• 作者：Thomas M. Beale ; Daniel M. Allwood ; Andreas Bender ; Peter J. Bond ; James D. Brenton ; D. Stephen Charnock-Jones ; Steven V. Ley ; Rebecca M. Myers ; James W. Shearman ; Jill Temple ; Jessica Unger ; Ciorsdaidh A. Watts ; Jian Xian
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2012
• 出版时间：March 8, 2012
• 年：2012
• 卷：3
• 期：3
• 页码：177-181
• 全文大小：281K
• 年卷期：v.3,no.3(March 8, 2012)
• ISSN：1948-5875

文摘

The combretastatins have been investigated for their antimitotic and antivascular properties, and it is widely postulated that a 3,4,5-trimethoxyaryl A-ring is essential to maintain potent activity. We have synthesized new tetrazole analogues (32鈥?b>34), demonstrating that 3,5-dihalogenation can consistently increase potency by up to 5-fold when compared to the equivalent trimethoxy compound on human umbilical vein endothelial cells (HUVECs) and a range of cancer cells. Moreover, this increased potency offsets that lost by installing the tetrazole bridge into combretastatin A-4 (1), giving crystalline, soluble compounds that have low nanomolar activity, arrest cells in G₂/M phase, and retain microtubule inhibitory activity. Molecular modeling has shown that optimized packing within the binding site resulting in increased Coulombic interaction may be responsible for this improved activity.

Keywords:

Combretastatin; tetrazole; dihalogenation; human umbilical vein endothelial cell; ovarian cancer; vascular disrupting agent