Submitted to: Bioorganic and Medicinal Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/23/2003
Publication Date: 5/1/2003
Citation: Dao, V., Dowd, M.K., Gaspard, C., Martin, M., Hemez, J., Laprevote, O., Mayer, M., Michelot, R. 2003. New thioderivatives of gossypol and gossypolone, as prodrugs of cytotoxic agents. Bioorganic and Medicinal Chemistry. 11(9):2001-2006.
Interpretive Summary: Gossypol is a natural product of the cotton plant that has a wide spectrum of bioactivity including anti-cancer effects. To study if derivatives of gossypol are more or less toxic to tumor cells, sulfur derivaties of gossypol were synthesized and tested for activity against carcinoma cells. The results indicate that the derivatives were less toxic to the tumor cells, but suggest that the compounds may be useful as prodrugs that become active near tumor cells surrounded by elevated concentrations of nitric oxide. The experiments will be useful to researchers studying the anti-cancer properties of gossypol.
Technical Abstract: New dithiane or dithiolane derivatives of gossypol and gossypolone were synthesized with dithioethane or dithiolpropane in the presence of boron trifloride and ethyl ether. These thioderivates exhibited low toxicity on KB cells (human epidermoid carcinoma cells of the mouth). They react easily with electrophiles in aprotic solvents to regenerate gossypolone or to form dehydrogossypoldithianes and dehydrogossypoldithiolanes, which display higher toxicity on KB cells. In addition, the low toxicity of gossypol thioderivatives was reversed with nitric oxide donors in physiological media. These experiments suggest that gossypol and gossypolone dithianes and dithiolanes can be used as prodrugs that target tumor cells surrounded by high concentrations of nitric oxide.