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

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 alpha-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 alpha-carbon. Cellular and supersomal studies showed that this alpha-substitution pattern controls the useful range of oxygen concentrations over which 1 can be effectively released by the prodrug.
AuthorsPeter Thomson, Matthew A Naylor, Steven A Everett, Michael R L Stratford, Gemma Lewis, Sally Hill, Kantilal B Patel, Peter Wardman, Peter D Davis
JournalMolecular cancer therapeutics (Mol Cancer Ther) Vol. 5 Issue 11 Pg. 2886-94 (Nov 2006) ISSN: 1535-7163 [Print] United States
PMID17121936 (Publication Type: Journal Article)
Chemical References
  • Antineoplastic Agents, Phytogenic
  • Nitro Compounds
  • Prodrugs
  • Stilbenes
  • Thiophenes
  • Tubulin
  • fosbretabulin
Topics
  • Animals
  • Antineoplastic Agents, Phytogenic (chemical synthesis, chemistry, metabolism)
  • Dose-Response Relationship, Drug
  • Humans
  • Liver (drug effects, metabolism)
  • Mice
  • Nitro Compounds (chemistry)
  • Prodrugs (chemical synthesis, chemistry, metabolism)
  • Stilbenes (chemistry, metabolism)
  • Thiophenes (chemical synthesis, chemistry)
  • Time Factors
  • Tubulin (drug effects, metabolism)
  • Tumor Cells, Cultured

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