Glutathione Peroxidase-like Antioxidant Activity of Diaryl Diselenides: A Mechanistic Study

The synthesis, structure, and thiol peroxidase-like antioxidant activities of several diaryl diselenides
having intramolecularly coordinating amino groups are described. The diselenides derived from enantiomerically
pure R-(+)- and S-(−)-N,N-dimethyl(1-ferrocenylethyl)amine show excellent peroxidase activity. To investigate
the mechanistic role of various organoselenium intermediates, a detailed in situ characterization of the
intermediates has been carried out by 77Se NMR spectroscopy. While most of the diselenides exert their
peroxidase activity via selenol, selenenic acid, and selenenyl sulfide intermediates, the differences in the relative
activities of the diselenides are due to the varying degree of intramolecular Se···N interaction. The diselenides
having strong Se···N interactions are found to be inactive due to the ability of their selenenyl sulfide derivatives
to enhance the reverse GPx cycle (RSeSR + H2O2 = RSeOH). In these cases, the nucleophilic attack of thiol
takes place preferentially at selenium rather than sulfur and this reduces the formation of selenol by terminating
the forward reaction. On the other hand, the diselenides having weak Se···N interactions are found to be more
active due to the fast reaction of the selenenyl sulfide derivatives with thiol to produce diphenyl disulfide and
the expected selenol (RSeSR + PhSH = PhSSPh + RSeH). The unsubstituted diaryl diselenides are found to
be less active due to the slow reactions of these diselenides with thiol and hydrogen peroxide and also due to
the instability of the intermediates. The catalytic cycles of 18 and 19 strongly resemble the mechanism by
which the natural enzyme, glutathione peroxidase, catalyzes the reduction of hydroperoxides.