Enol-mediated delivery of H(2)Se from γ-keto selenides: mechanistic insight and evaluation

Like hydrogen sulfide (H(2)S), its chalcogen congener, hydrogen selenide (H(2)Se), is an emerging molecule of interest given its endogenous expression and purported biological activity. However, unlike H(2)S, detailed investigations into the chemical biology of H(2)Se are limited and little is known about its innate physiological functions, cellular targets, and therapeutic potential. The obscurity surrounding these fundamental questions is largely due to a lack of small molecule donors that can effectively increase the bioavailability of H(2)Se through their continuous liberation of the transient biomolecule under physiologically relevant conditions. Driven by this unmet demand for H(2)Se-releasing moieties, we report that γ-keto selenides provide a useful platform for H(2)Se donation via an α-deprotonation/β-elimination pathway that is highly dependent on both pH and alpha proton acidity. These attributes afforded a small library of donors with highly variable rates of release (higher alpha proton acidity = faster selenide liberation), which is accelerated under neutral to slightly basic conditions—a feature that is unique and complimentary to previously reported H(2)Se donors. We also demonstrate the impressive anticancer activity of γ-keto selenides in both HeLa and HCT116 cells in culture, which is likely to stimulate additional interest and research into the biological activity and anticancer effects of H(2)Se. Collectively, these results indicate that γ-keto selenides provide a highly versatile and effective framework for H(2)Se donation.