Gem-Dimethyl Selenoketal: Suppressing Sulfur-Selenium Exchange 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.