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.
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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 |
Journal | Molecular cancer therapeutics
(Mol Cancer Ther)
Vol. 5
Issue 11
Pg. 2886-94
(Nov 2006)
ISSN: 1535-7163 [Print] United States |
PMID | 17121936
(Publication Type: Journal Article)
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Chemical References |
- Antineoplastic Agents, Phytogenic
- Nitro Compounds
- Prodrugs
- Stilbenes
- Thiophenes
- Tubulin
- fosbretabulin
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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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