Studies on the mechanisms of activation of indolequinone phosphoramidate prodrugs.
Previously a series of 2- and 3-substituted indolequinone phosphoramidate prodrugs was synthesized, and the compounds were shown to be nanomolar inhibitors of cell proliferation. The activation of these compounds following both one- and two-electron reduction has been investigated. (31)P NMR experiments demonstrated that both series of compounds undergo rapid activation following two-electron reduction. Additionally, the 3-series of compounds undergo rapid activation following one-electron reduction, while activation of the 2-series of compounds via this mechanism is very slow. The activation of these prodrugs by direct displacement using sulfur nucleophiles such as glutathione has been examined. Activation via this route is rapid for the 3-regioisomers, but is considerably slower for the 2-substituted analogues under similar conditions. Together these findings suggest that drug delivery via two-electron reduction from the 2-position is the more selective prodrug strategy.
Hernick
Marcy
M
Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 47907, USA.
Borch
Richard F
RF
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000528:radiation effects; D009682:Magnetic Resonance Spectroscopy; D009943:Organophosphorus Compounds / Q000737:chemistry* / Q000528:radiation effects; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000737:chemistry* / Q000528:radiation effects; D011809:Quinones / Q000737:chemistry* / Q000528:radiation effects; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D009943:Organophosphorus Compounds; D011355:Prodrugs; D011809:Quinones