Cleavage of a Peroxide Bond via a Dual Attack by Functional Mimics of Glutathione Peroxidase.

Nonmetal-containing peroxidase enzymes, including glutathione peroxidase (GPx), and peroxiredoxins, control cellular redox levels by catalyzing the reduction of HO. The remarkably higher reactivity of GPx enzyme as compared to the fully dissociated synthetic selenolate/thiolate molecule is probably due to the dual-attack on the peroxide bond (HO-OH) by the enzyme; The first one is a nucleophilic attack of the selenolate/thiolate moiety to O atom and the second attack at the O atom of the peroxide bond by the acidic "parked proton" from Trp or His residue present at the enzyme's active site, leading to the facile cleavage of O-O bond. Herein, we report two synthetic compounds (1 and 2), having a selenolate (Se) and a proton donor (imidazolium or -COOH group) moieties, which showed excellent GPx-like activity via dual-attack on the peroxide bond. The combined effect of selenolate moiety that donates electrons to the antibonding (σ*) orbital of O-O bond and the imidazolium or carboxylic acid moiety at the side chain that forms a strong H-bonding with the O atom facilitates O-O bond cleavage of HO more efficiently. 1 and 2 exhibit remarkable ability in protecting Cu(I)-complex [TpmCu(CHCN)] (9) against HO by acting as a sacrificial antioxidant, thereby preventing metal-mediated ROS production.