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.
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Authors | 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 |
Journal | ACS medicinal chemistry letters
(ACS Med Chem Lett)
Vol. 3
Issue 3
Pg. 177-81
(Mar 08 2012)
ISSN: 1948-5875 [Print] United States |
PMID | 24900453
(Publication Type: Journal Article)
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