Activation energies of selenoxide elimination from Se-substituted selenocysteine

Transition states for selenoxide elimination have been determined for a series of Se-substituted selenocysteine (RSeCys) derivatives that have potential use in the prevention and treatment of cancer, either directly or in conjunction with cisplatin (to reduce its nephrotoxic effects). Reduced activation barriers vs R=Me and R=Ph are found when the alkyl chain length is increased or when activating groups are para to the selenide. Ortho substitution of Lewis bases stabilizes the transition state by directly donating electron density to the selenoxide. The results suggest that RSeCys derivatives incorporating the properties of glutathione peroxidase mimics will, upon oxidation, rapidly eliminate selenenic acid, a precursor to chemopreventative selenols.