Gem-DimethylSelenoketal: Suppressing Sulfur–SeleniumExchange with Antioxidant and Anti-Inflammatory Activities

Although organoselenium compounds offer unique advantages in antioxidant defense and immune regulation, their inherent high reactivity toward biological thiols leads to nonspecific selenium–sulfur exchange reactions in vivo, resulting in off-target biotoxicity and significantly hindering their applications. Herein, we report a novel diselenium ketal diamine (SEK) to address these challenges by integrating biocompatibility, antioxidant activity, and immunomodulatory function into a single molecule. By incorporating a gem-dimethyl group via acetone condensation, SEK suppressed Se–S exchange through steric stabilization, increasing its half maximal inhibitory concentration (IC50) to 75.5 μM, which was 10-fold higher than that of its diselenide precursor (7.6 μM). SEK exhibited rapid and reversible redox reactivity toward oxidants and free radicals. It reacted rapidly with H2O2 to form O2SEK, a stable diselenoxide intermediate stabilized by intramolecular Se═O···H–N hydrogen bonding, and was reversibly reduced by glutathione, ultimately reducing intracellular H2O2 levels by 40% in inflammatory microenvironments. SEK promoted polarization of immune cells toward an anti-inflammatory phenotype under oxidative stress by upregulating selenoprotein expression, resulting in a 40% decrease in pro-inflammatory M1 cell populations and a concomitant >30% reduction in pro-inflammatory cytokine secretion. This novel diselenium ketal overcomes the limitations of traditional organoselenium compounds by suppressing nonspecific Se–S exchange and exerting synergistic antioxidant-anti-inflammatory regulatory effects, paving the way for advances in bioactive organoselenium chemistry.