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

Abstract

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.

H2S attenuates acute lung inflammation induced by administration of lipopolysaccharide in adult male rats

“…All previous mechanisms concerning the effects of both H 2 S and its products; polysulfides on ROS production and antioxidant gene expression are compatible with the decreased lung lipid peroxides associated with increased lung TAC levels in our results which is also in agreement with Campos et al (2016), Zhang et al (2016), Li et al (2016) and Song and Wang (2016). Kang et al (2017) reported that H 2 S decreased proinflammatory cytokines by suppressing the activation of NF-κB and MAPK dependent signaling and this is compatible with decreased serum IL-6 level with NaHS administration in the current study. A previous study documented that H 2 S donor could inhibit the activity of NF-κB by inhibiting the degradation of its inhibitor nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα).…”

Hydrogen sulfide inhibits aortic valve calcification in heart via regulating RUNX2 by NF-κB, a link between inflammation and mineralization

“…AP72 has an excellent water solubility and very slow generation of H 2 S compared to the fast H 2 S releasing donors such as Na 2 S and NaSH [28] , [44] , [45] . It is increasingly recognized that slow-releasing H 2 S donors potentially better mimic the effects of the endogenous H 2 S buffer system, because of their slow generation of low sulfide levels [24] , [28] , [29] .…”

The Potential Role of Hydrogen Sulfide in the Regulation of Cerebrovascular Tone

“…These donors lead to extremely high levels of H 2 S immediately after their administration and then the level decreases rapidly resulting in highly fluctuating H 2 S concentrations [ 62 ]. The slow-releasing donors (GYY4137, and its further derivatives) provide a more reliable dosage and a more sustained level of H 2 S during treatment [ 63 , 64 ]. Interestingly, only one study about the cerebrovascular effect of H 2 S included measurements with GYY4137 and according to the results of this publication, GYY4137 had the smallest effect on vascular tone compared to the fast-releasing compounds NaHS and Na 2 S [ 50 ].…”