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

Beale, T. M. et al. (2012) A-ring dihalogenation increases the cellular activity of combretastatin-templated tetrazoles. ACS Medicinal Chemistry Letters, 3(3), pp. 177-181. (doi: 10.1021/ml200149g)

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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.

Item Type:Articles
Glasgow Author(s) Enlighten ID:Watts, Dr Ciorsdaidh
Authors: Beale, T. M., Allwood, D. M., Bender, A., Bond, P. J., Brenton, J. D./, Charnock-Jones, D. S., Ley, S. V., Myers, R. M., Shearman, J. W., Temple, J., Unger, J., Watts, C. A., and Xian, J.
College/School:College of Science and Engineering > School of Chemistry
Journal Name:ACS Medicinal Chemistry Letters
Publisher:American Chemical Society

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