Enol-mediated delivery of H2Se from γ-keto selenides: mechanistic insight and evaluation

Abstract

Like hydrogen sulfide (H₂S), its chalcogen congener, hydrogen selenide (H₂Se), is an emerging molecule of interest given its endogenous expression and purported biological activity. However, unlike H₂S, detailed investigations into the chemical biology of H₂Se 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 H₂Se through their continuous liberation of the transient biomolecule under physiologically relevant conditions. Driven by this unmet demand for H₂Se-releasing moieties, we report that γ-keto selenides provide a useful platform for H₂Se 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 H₂Se 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 H₂Se. Collectively, these results indicate that γ-keto selenides provide a highly versatile and effective framework for H₂Se donation.