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

Journal article

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.

Authors: Thomson, P; Naylor, M; Everett, SA; Stratford, MR; Lewis, G

• Publication status: Published
• Journal: Molecular cancer therapeutics
• Volume: 5
• Issue: 11
• Pages: 2886-2894
• Publication date: 2006-11-01
• DOI: 10.1158/1535-7163.mct-06-0429
• EISSN: 1538-8514
• ISSN: 1535-7163
• Language: English
• Keywords: Dose-Response Relationship, Drug; Antineoplastic Agents, Phytogenic; Tumor Cells, Cultured; Tubulin; Liver; Thiophenes; Nitro Compounds; Time Factors; Prodrugs; Humans; Animals; Mice; Stilbenes