Reactive sulfur species (RSS) are biologically important molecules. Among them, H S, hydrogen polysulfides (H S n>1), persulfides (RSSH), and HSNO are believed to play regulatory roles in sulfur-related redox biology. However, these molecules are unstable and difficult to handle. Having access to their reliable and controllable precursors (or donors) is the prerequisite for the study of these sulfur species. Reported in this work is the preparation and evaluation of a series of O-silyl-mercaptan-based sulfur-containing molecules which undergo pH- or F -mediated desilylation to release the corresponding H S, H S , RSSH, and HSNO in a controlled fashion. This O→S relay deprotection serves as a general strategy for the design of pH- or F -triggered RSS donors. Moreover, we have demonstrated that the O-silyl groups in the donors could be changed into other protecting groups like esters. This work should allow the development of RSS donors with other activation mechanisms (such as esterase-activated donors).

Metrics & More Article Recommendations CONSPECTUS: Reactive sulfur species (RSS) play regulatory roles in many physiological and pathological processes. Since the discovery of hydrogen sulfide (H 2 S) as a nitric oxide (NO)-like signaling molecule, understanding the chemical biology of H 2 S and H 2 S-related RSS, such as hydropersulfides (RSSH) and polysulfides (H 2 S 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 H 2 S in a controllable fashion. These studies led to the discovery of a series of novel H 2 S donors. We later expanded our interests to other RSS including RSSH, H 2 S 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 H 2 S-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. ■ KEY REFERENCES• Zhao, Y.; Wang, H.; Xian, M. Cysteine-activated hydrogen sulfide (H 2 S) donors. J. Am. Chem. Soc. 2011, 133, 15−17. 1 The concept of controlled H 2 S donors is formulated for the f irst time.

Reactive sulfur species (RSS) are biologically important molecules. Among them, H2S, hydrogen polysulfides (H2Sn, n>1), persulfides (RSSH), and HSNO are believed to play regulatory roles in sulfur‐related redox biology. However, these molecules are unstable and difficult to handle. Having access to their reliable and controllable precursors (or donors) is the prerequisite for the study of these sulfur species. Reported in this work is the preparation and evaluation of a series of O‐silyl‐mercaptan‐based sulfur‐containing molecules which undergo pH‐ or F−‐mediated desilylation to release the corresponding H2S, H2Sn, RSSH, and HSNO in a controlled fashion. This O→S relay deprotection serves as a general strategy for the design of pH‐ or F−‐triggered RSS donors. Moreover, we have demonstrated that the O‐silyl groups in the donors could be changed into other protecting groups like esters. This work should allow the development of RSS donors with other activation mechanisms (such as esterase‐activated donors).

In this work, we carried out computational studies to predict the cycloaddition efficiency of strained alkynes with 2H-pyran-2-one and its three sulfur-containing analogues: 2H-pyran-2-thione, 2H-thiopyran-2-one, and 2H-thiopyran-2-thione. It was predicted that the decreased aromaticity of the substrate would yield higher reactivity. Experimental studies confirmed the calculation results, and 2H-pyan-2-thiones were found to be the most reactive substrates. This reaction proceeded effectively in aqueous buffers and in cellular environments. It also produced COS as the byproduct, which could be converted into hydrogen sulfide (H2S) in the presence of carbonate anhydrase. This click-and-release approach may serve as a unique way to deliver COS/H2S to specific locations.

Oxidation of α-siloxy thioethers leads to the formation of the corresponding sulfoxides as unstable intermediates, which undergo an intramolecular oxygen-to-oxygen silyl migration to break the C–S linkage. This process produces silyl protected sulfenic acids and subsequently thiosulfinates. It was used to develop oxidation-triggered allicin donors.