Activatable Small-Molecule Hydrogen Sulfide Donors

Hydrogen sulfide (HS) is an important biological signaling molecule involved in many physiological processes. These diverse roles have led researchers to develop contemporary methods to deliver HS under physiologically relevant conditions and in response to various stimuli. Different small-molecule donors have been developed that release HS under various conditions. Key examples include donors activated in response to hydrolysis, to endogenous species, such as thiols, reactive oxygen species, and enzymes, and to external stimuli, such as photoactivation and bio-orthogonal chemistry. In addition, an alternative approach to release HS has utilized the catalyzed hydrolysis of carbonyl sulfide (COS) by carbonic anhydrase to generate libraries of activatable COS-based HS donors. Small-molecule HS donors provide important research and pharmacological tools to perturb HS levels. Key needs, both in the development and in the use of such donors, include access to new donors that respond to specific stimuli as well as donors with well-defined control compounds that allow for clear delineation of the impact of HS delivery from other donor byproducts. The abundance of reported small-molecule HS donors provides biologists and physiologists with a chemical toolbox to ask key biological questions and to develop HS-related therapeutic interventions. Further investigation into different releasing efficiencies in biological contexts and a clear understanding of biological responses to donors that release HS gradually (, hours to days) donors that generate HS quickly (, seconds to minutes) is needed.