Phosphonothioate-Based Hydrogen Sulfide Releasing Reagents: Chemistry and Biological Applications

Hydrogen sulfide (H₂S) is a newly recognized gasotransmitter. Studies have demonstrated that the production of endogenous H₂S and the exogenous administration of H₂S can regulate many physiological and/or pathological processes. Therefore, H₂S releasing agents (also known as H₂S donors) are important research tools in advancing our understanding of the biology and clinical potential of H₂S. Among currently available donors, GYY4137 is probably the most well-known and has been used in many studies in the past 10 years. Recently, a number of GYY4137 derivatives (e.g., phosphonothioate-based compounds) have been developed as H₂S donors. In this review, we summarize the development and application of these donors, which include Lawesson's reagent, substituted phosphorodithioates, cyclic phosphorane analogs, and pH-controlled phosphonamidothioates (JK donors). These donors have advantages such as good water-solubility, slow and controllable H₂S release capability, and a variety of reported biological activities. However, it should be noted that the detailed H₂S release profiles and byproducts under real biological systems are still unclear for many of these donors. Only after we figure out these unknowns we will see better applications of these donors in H₂S research and therapy.