Hydrogen selenide (H2Se) is an important metabolite in selenium biochemistry and plays a crucial role in redox biology. While its significance has become increasingly recognized, research on H2Se is challenging due to its instability and high reactivity. Suitable compounds (aka donors) that can selectively produce H2Se in biological systems would facilitate this research field. In this work, we explored photo-triggered H2Se donors by utilizing two structural templates: 2-nitrobenzyl selenides and 2-methoxy-6-naphthacyl selenides. The photoreactions of these compounds under light were studied. 2-Nitrobenzyl selenides were found to release H2Se (and its oxidized form H2Se2) slowly under UV light, but the released H2Se/H2Se2 could further react with the photoproduct and be consumed. On the other hand, naphthacyl selenides could undergo clean and fast reactions to produce H2Se/H2Se2, as well as a stable and fluorescent photoproduct. This self-monitoring and quick releasing ability make naphthacyl selenides ‛smart donors’ for biological applications. Importantly, this donor was found to induce protein S-selenylation (CysS-SeH) on Cys47 and Cys91 in both recombinant peroxiredoxin-6 (PRDX6) and PRDX6-overexpressing HEK293T cells. This photo-triggered donor system may serve as a new strategy to control selenium-based protein post-translational modifications for mechanistic studies into selenium metabolic pathways and ferroptosis.
