Phototriggered Hydrogen Persulfide Donors via Hydrosulfide Radical Formation Enhancing the Reactive Sulfur Metabolome in Cells

Hydrogen persulfide (H₂S₂) is an important sulfur-containing signaling molecule that plays a crucial role in the homeostasis of various organ systems, such as the renal, cardiovascular, liver, and gastrointestinal systems. However, research on H₂S₂ in biological settings is still challenging due to its instability and high reactivity. Compounds that can controllably release H₂S₂ (also known as donors) are thus crucial research tools. Currently, available H₂S₂ donors are still very limited, with most of them relying on modified disulfide templates. These templates possess an unavoidable limitation of being susceptible to cellular disulfide exchange which can compromise their efficacy. In this work, we explored nondisulfide-based and nonoxidation-dependent templates for the design of H₂S₂ donors. We found that tertiary naphthacyl thiols could undergo phototriggered C-S homolytic cleavage to form H₂S₂ via hydrosulfide (HS) radicals. In addition, the release of H₂S₂ was associated with the formation of a product with strong blue fluorescence, which allowed for real-time monitoring of the release process. This reaction was demonstrated to proceed effectively in both buffers and cells, with the ability to enhance intracellular production of persulfides, including GSSH, CysSSH, H₂S₂, H₂S₃, etc. It provides a unique photocontrolled H₂S₂ donor system with distinct advantages compared to known H₂S₂ donors due to its good stability and spatiotemporal control ability.