Cleavage of a Peroxide Bond <i>via</i> 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 H₂O₂. 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 (HO¹-O²H) by the enzyme; The first one is a nucleophilic attack of the selenolate/thiolate moiety to O¹ atom and the second attack at the O² 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 O¹-O² bond and the imidazolium or carboxylic acid moiety at the side chain that forms a strong H-bonding with the O² atom facilitates O-O bond cleavage of H₂O₂ more efficiently. 1 and 2 exhibit remarkable ability in protecting Cu(I)-complex [TpmCu(CH₃CN)]⁺ (9) against H₂O₂ by acting as a sacrificial antioxidant, thereby preventing metal-mediated ROS production.