Phototriggered Hydrogen\nPersulfide Donors via Hydrosulfide\nRadical Formation Enhancing the Reactive Sulfur Metabolome in Cells

Hydrogen persulfide (H<sub>2</sub>S<sub>2</sub>) is an\nimportant\nsulfur-containing signaling molecule that plays a crucial role in\nthe homeostasis of various organ systems, such as the renal, cardiovascular,\nliver, and gastrointestinal systems. However, research on H<sub>2</sub>S<sub>2</sub> in biological settings is still challenging due to\nits instability and high reactivity. Compounds that can controllably\nrelease H<sub>2</sub>S<sub>2</sub> (also known as donors) are thus\ncrucial research tools. Currently, available H<sub>2</sub>S<sub>2</sub> donors are still very limited, with most of them relying on modified\ndisulfide templates. These templates possess an unavoidable limitation\nof being susceptible to cellular disulfide exchange which can compromise\ntheir efficacy. In this work, we explored nondisulfide-based and nonoxidation-dependent\ntemplates for the design of H<sub>2</sub>S<sub>2</sub> donors. We\nfound that tertiary naphthacyl thiols could undergo phototriggered\nC–S homolytic cleavage to form H<sub>2</sub>S<sub>2</sub> via\nhydrosulfide (HS) radicals. In addition, the release of H<sub>2</sub>S<sub>2</sub> was associated with the formation of a product with\nstrong blue fluorescence, which allowed for real-time monitoring of\nthe release process. This reaction was demonstrated to proceed effectively\nin both buffers and cells, with the ability to enhance intracellular\nproduction of persulfides, including GSSH, CysSSH, H<sub>2</sub>S<sub>2</sub>, H<sub>2</sub>S<sub>3</sub>, etc. It provides a unique photocontrolled\nH<sub>2</sub>S<sub>2</sub> donor system with distinct advantages compared\nto known H<sub>2</sub>S<sub>2</sub> donors due to its good stability\nand spatiotemporal control ability.