title: 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.
authors.affiliation: Department of Chemistry, Lensfield Road, University of Cambridge , Cambridge CB2 1EW, U.K.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Beale
authors.affiliation: Department of Chemistry, Lensfield Road, University of Cambridge , Cambridge CB2 1EW, U.K.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Allwood
authors.affiliation: Unilever Centre for Molecular Science Informatics, Lensfield Road, University of Cambridge , Cambridge CB2 1EW, U.K.
authors.forename: Andreas
authors.initials: A
authors.lastname: Bender
authors.affiliation: Unilever Centre for Molecular Science Informatics, Lensfield Road, University of Cambridge , Cambridge CB2 1EW, U.K.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bond
authors.affiliation: Functional Genomics of Ovarian Cancer Laboratory, Cancer Research U.K., Cambridge Research Institute , Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, U.K.
authors.forename: James D
authors.initials: JD
authors.lastname: Brenton
authors.affiliation: Department of Obstetrics and Gynaecology, University of Cambridge , and National Institute for Health Research, Cambridge Comprehensive Biomedical Research Centre, Cambridge CB2 0SW, U.K.
authors.forename: D Stephen
authors.initials: DS
authors.lastname: Charnock-Jones
authors.affiliation: Department of Chemistry, Lensfield Road, University of Cambridge , Cambridge CB2 1EW, U.K.
authors.forename: Steven V
authors.initials: SV
authors.lastname: Ley
authors.affiliation: Department of Chemistry, Lensfield Road, University of Cambridge , Cambridge CB2 1EW, U.K.
authors.forename: Rebecca M
authors.initials: RM
authors.lastname: Myers
authors.affiliation: Department of Chemistry, Lensfield Road, University of Cambridge , Cambridge CB2 1EW, U.K.
authors.forename: James W
authors.initials: JW
authors.lastname: Shearman
authors.affiliation: Functional Genomics of Ovarian Cancer Laboratory, Cancer Research U.K., Cambridge Research Institute , Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, U.K.
authors.forename: Jill
authors.initials: J
authors.lastname: Temple
authors.affiliation: Functional Genomics of Ovarian Cancer Laboratory, Cancer Research U.K., Cambridge Research Institute , Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, U.K.
authors.forename: Jessica
authors.initials: J
authors.lastname: Unger
authors.affiliation: Department of Chemistry, Lensfield Road, University of Cambridge , Cambridge CB2 1EW, U.K.
authors.forename: Ciorsdaidh A
authors.initials: CA
authors.lastname: Watts
authors.affiliation: Functional Genomics of Ovarian Cancer Laboratory, Cancer Research U.K., Cambridge Research Institute , Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, U.K.
authors.forename: Jian
authors.initials: J
authors.lastname: Xian
keywords: Combretastatin; dihalogenation; human umbilical vein endothelial cell; ovarian cancer; tetrazole; vascular disrupting agent