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A-ring dihalogenation increases the cellular activity of combretastatin-templated tetrazoles.

Abstract
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 (32-34), 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.
AuthorsThomas 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
JournalACS medicinal chemistry letters (ACS Med Chem Lett) Vol. 3 Issue 3 Pg. 177-81 (Mar 08 2012) ISSN: 1948-5875 [Print] United States
PMID24900453 (Publication Type: Journal Article)

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