Hydrogen sulfide (HS) is a ubiquitous small gaseous signaling molecule, playing an important role in many physiological processes and joining nitric oxide and carbon monoxide in the group of signaling agents termed gasotransmitters. Endogenous concentrations of HS are generally low, making it difficult to discern precise biological functions. As such, probing the physiological roles of HS is aided by exogenous delivery of the gas in cell and animal studies. This need for an exogenous source of HS provides a unique challenge for chemists to develop chemical tools that facilitate the study of HS under biological conditions. Compounds that degrade in response to a specific trigger to release HS, termed HS donors, include a wide variety of functional groups and delivery systems, some of which mimic the tightly controlled endogenous production in response to specific, biologically relevant conditions. This review examines a variety of HS donor systems classified by their HS-releasing trigger as well as their HS release profiles, byproducts, and potential therapeutic applications.

We report the facile preparation of a family of S-aroylthiooxime (SATO) H2S donors, which are synthesized via a click reaction analogous to oxime formation between S-aroylthiohydroxylamines (SATHAs) and aldehydes or ketones. Analysis of cysteine-triggered H2S release revealed structure-dependent release kinetics with half-lives from 8-82 min by substitution of the SATHA ring. The pseudo-first-order rate constants of substituted SATOs fit standard linear free energy relationships (ρ = 1.05), demonstrating a significant sensitivity to electronic effects.

Carbonyl sulfide (COS) is a gas that may play important roles in mammalian and bacterial biology, but its study is limited by a lack of suitable donor molecules. We report here the use of N-thiocarboxyanhydrides (NTAs) as COS donors that release the gas in a sustained manner under biologically relevant conditions with innocuous peptide byproducts. Carbonic anhydrase converts COS into H2S, allowing NTAs to serve as either COS or H2S donors, depending on the availability of the enzyme. Analysis of the pseudo-first-order H2S release rate under biologically relevant conditions revealed a release half-life of 75 min for the small molecule NTA under investigation. A polynorbornene bearing pendant NTAs made by ring-opening metathesis polymerization was also synthesized to generate a polymeric COS/H2S donor. A half-life of 280 min was measured for the polymeric donor. Endothelial cell proliferation studies revealed an enhanced rate of proliferation for cells treated with the NTA over untreated controls.

Persulfides (RSSH) have been hypothesized as critical components in sulfur-mediated redox cycles and as potential signaling compounds, similar to hydrogen sulfide (H S). Hindering the study of persulfides is a lack of persulfide-donor compounds with selective triggers that release discrete persulfide species. Reported here is the synthesis and characterization of a ROS-responsive (ROS=reactive oxygen species), self-immolative persulfide donor. The donor, termed BDP-NAC, showed selectivity towards H O over other potential oxidative or nucleophilic triggers, resulting in the sustained release of the persulfide of N-acetyl cysteine (NAC) over the course of 2 h, as measured by LCMS. Exposure of H9C2 cardiomyocytes to H O revealed that BDP-NAC mitigated the effects of a highly oxidative environment in a dose-dependent manner over relevant controls and to a greater degree than common H S donors sodium sulfide (Na S) and GYY4137. BDP-NAC also rescued cells more effectively than a non-persulfide-releasing control compound in concert with common H S donors and thiols.

We report a synthetic route toward a family of functional COS/H 2 S-releasing N-substituted Nthiocarboxyanhydrides (NTAs) with functionalities to accommodate popular conjugation reactions, including olefin cross metathesis, thiol-ene, and copper-catalyzed azide-alkyne cycloaddition. The N-substituted NTAs were attached to small molecules, polymers, and a protein to synthesize novel H 2 S donors convergently. All conjugates showed sustained H 2 S release kinetics.