Abstract:
Hydrogen sulfide is now recognized as a gasotransmitter along with Nitric oxide (NO) and Carbon monoxide (CO) because of its involvement in signaling pathways, biological applications and the therapeutic role it plays. Most of the H2S donors used in the biological studies do not mimic the slow and continuous release of H2S in cells which is enzyme triggered rather, they release H2S rapidly and in an uncontrolled manner. The biological functions of H2S are highly correlated with the rate of release of H2S as evidenced by the contrasting roles it plays in inflammatory pathways and in cancer therapy. The study presented here includes synthesis and evaluation of kinetics of small molecule H2S donors which can be triggered by oxidative stress. Oxidative stress is a which is a biological state in which there is an imbalance in antioxidants and ROS (reactive oxygen species) produced as part of cellular metabolism. Upon activation by H2O2 the compounds undergo self-immolation to generate H2S in the presence of carbonic anhydrase which is widely present in cells. It was hypothesized that changing the substitution on the nitrogen can vary the rate of release of H2S. This would be dependent on the leaving group. The kinetics of release of H2S from the donors was studied independently using methylene blue assay and HPLC. In accordance with the proposed hypothesis, varying the leaving group shows an effect on rates of release of H2S upon activation by H2O2. Donors with group on the nitrogen having lower pKa showed a significantly higher rate compared to donors with higher pKa values. By varying the amines on the carbamothioate, we were able to achieve a tunable release of H2S in the range of 13-204 min as half-lives. This study also includes small molecule H2S donors which can release H2S in a slow and continuous manner with half-lives comparable with macromolecule H2S donors with reasonable yields.
