Deazapurine-Based Cyclic Selenenyl Sulfide as a Glutathione Peroxidase Mimetic

Glutathione peroxidase (GPx) is a vital antioxidant enzyme that protects cells from oxidative damage by catalyzing the reduction of reactive oxygen species (ROS). The development of efficient GPx mimetics is crucial for reproducing this protective function in therapeutic and industrial contexts. In this study, we describe the gram-scale synthesis of a water-soluble deazapurine-based cyclic selenenyl sulfide via an efficient five-step route. The catalytic activity of this compound was evaluated under physiologically relevant glutathione (GSH) concentrations (∼6.5 mM). Activity was quantified using a newly developed UPLC-based assay and benchmarked against results obtained with the classical NMR-based Iwaoka assay, ensuring cross-validation of kinetic parameters. Using these complementary approaches, we demonstrate that the selenenyl sulfide 6a catalyzes thiol oxidation with substantially higher efficiency than ebselen, a widely studied GPx mimic, under applied assay conditions. In addition, the compound exhibits exceptional chemical stability, with no NMR-detectable signs of degradation after two years of storage. These findings underscore the potential of cyclic selenenyl sulfides as GPx mimetics, providing a strong rationale for evaluating their catalytic properties in more complex chemical and biological contexts.