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Research Articles: Therapeutics, Targets, and Development

Synthesis and biological properties of bioreductively targeted nitrothienyl prodrugs of combretastatin A-4

¹ University of Oxford, Gray Cancer Institute, Mount Vernon Hospital, Northwood, Middlesex, United Kingdom and ² Angiogene Pharmaceuticals Ltd., The Magdalen Centre, Oxford Science Park, Oxon, United Kingdom

Requests for reprints: Peter Thomson, Gray Cancer Institute, University of Oxford, Mount Vernon Hospital, Northwood, Middlesex, United Kingdom HA6 2JR. Phone: 441923828611. E-mail: thomson{at}gci.ac.uk

Abstract

Nitrothienylprop-2-yl ether formation on the 3'-phenolic position of combretastatin A-4 (1) abolishes the cytotoxicity and tubulin polymerization-inhibitory effects of the drug. 5-Nitrothiophene derivatives of 1 were synthesized following model kinetic studies with analogous coumarin derivatives, and of these, compound 13 represents a promising new lead in bioreductively targeted cytotoxic anticancer therapies. In this compound, optimized gem-dimethyl -carbon substitution enhances both the aerobic metabolic stability and the efficiency of hypoxia-mediated drug release. Only the gem-substituted derivative 13 released 1 under anoxia in either in vitro whole-cell experiments or supersomal suspensions. The rate of release of 1 from the radical anions of these prodrugs is enhanced by greater methyl substitution on the -carbon. Cellular and supersomal studies showed that this -substitution pattern controls the useful range of oxygen concentrations over which 1 can be effectively released by the prodrug. [Mol Cancer Ther 2006;5(11):2886–94]

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Received 7/21/06; revised 9/ 1/06; accepted 9/25/06.