The Path to Controlled Delivery of Reactive Sulfur Species

Reactive sulfur species (RSS) play regulatory roles in many physiological and pathological processes. Since the discovery of hydrogen sulfide (H₂S) as a nitric oxide (NO)-like signaling molecule, understanding the chemical biology of H₂S and H₂S-related RSS, such as hydropersulfides (RSSH) and polysulfides (H₂S_n), has become a fast-growing research field. However, the research on these RSS has technical difficulties due to their high reactivity and instability. To solve this problem, considerable efforts have been put into the development of unique RSS releasing compounds (e.g., donors) or in situ RSS generation systems. This Account tells the story of our research group's effort to develop novel RSS donors.We began with exploring molecular entities that were stable by themselves but could be triggered by biologically relevant factors, such as pH, thiols, light, or enzymes, to release H₂S in a controllable fashion. These studies led to the discovery of a series of novel H₂S donors. We later expanded our interests to other RSS including RSSH, H₂S_n, RSeSH, HSNO, RSOH, etc. The fundamental chemistry of these RSS was studied and applied to the development of the corresponding donors. In addition to small molecule donors, we also worked on H₂S-releasing biomaterials and their applications. This Account summarizes our work and systematically explains how each RSS donor template was proposed and evaluated. The Account covers the following key points: (1) rational chemistry design of each RSS donor template, (2) evaluation and mechanistic insights of each donor template, and (3) properties and biological applications of the donors.