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.