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

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

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Authors

  • Peter Thomson
  • Matthew A. Naylor
  • Steven A. Everett
  • Michael R. L. Stratford
  • Gemma Lewis
  • Sally Hill
  • Kantilal B. Patel
  • Peter Wardman
  • Peter D. Davis

Info

Original languageEnglish
Pages (from-to)2886-2894
Number of pages9
JournalMolecular Cancer Therapeutics
Volume5
Issue number11
DOIs
StatePublished - Nov 2006

Abstract

NOTE: THE MATHEMATICAL SYMBOLS IN THIS ABSTRACT CANNOT BE DISPLAYED CORRECTLY ON THIS PAGE. PLEASE REFER TO THE PUBLISHER'S WEBSITE FOR AN ACCURATE DISPLAY. 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 followingmodel kinetic studies with analogous coumarin derivatives, and of these, compound 13 represents a promisingnew lead in bioreductively targeted cytotoxic anticancer therapies. In this compound, optimized gemdimethyl a-carbon substitution enhances both the aerobic metabolic stability and the efficiency of hypoxia-mediated drugrel ease. 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 a-carbon. Cellular and supersomal studies showed that this a-substitution pattern controls the useful range of oxygen concentrations over which 1 can be effectively released by the prodrug.

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