2. Academic Validation
  3. A-ring dihalogenation increases the cellular activity of combretastatin-templated tetrazoles

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

  • ACS Med Chem Lett. 2012 Jan 19;3(3):177-81. doi: 10.1021/ml200149g.
Thomas M Beale 1,  Daniel M Allwood 1,  Andreas Bender 2,  Peter J Bond 2,  James D Brenton 3,  D Stephen Charnock-Jones 4,  Steven V Ley 1,  Rebecca M Myers 1,  James W Shearman 1,  Jill Temple 3,  Jessica Unger 3,  Ciorsdaidh A Watts 1,  Jian Xian 3
Affiliations

Affiliations

  • 1 Department of Chemistry, Lensfield Road, University of Cambridge , Cambridge CB2 1EW, U.K.
  • 2 Unilever Centre for Molecular Science Informatics, Lensfield Road, University of Cambridge , Cambridge CB2 1EW, U.K.
  • 3 Functional Genomics of Ovarian Cancer Laboratory, Cancer Research U.K., Cambridge Research Institute , Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, U.K.
  • 4 Department of Obstetrics and Gynaecology, University of Cambridge , and National Institute for Health Research, Cambridge Comprehensive Biomedical Research Centre, Cambridge CB2 0SW, U.K.
PMID: 24900453 DOI: 10.1021/ml200149g
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.

Keywords

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

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