Controllable thioester-based hydrogen sulfide slow-releasing donors as cardioprotective agents

Abstract

Hydrogen sulfide (H₂S) is an important signaling molecule with promising protective effects in many physiological and pathological processes. However, the study of H₂S has been impeded by the lack of appropriate H₂S donors that could mimic its slow-releasing process in vivo. Herein, we report the rational design, synthesis, and biological evaluation of a series of thioester-based H₂S donors. These cysteine-activated H₂S donors release H₂S in a slow and controllable manner. Most of the donors comprising an allyl moiety showed significant cytoprotective effects in H9c2 cellular models of oxidative damage. The most potent donor 5e decreased the mitochondrial membrane potential (MMP) loss and lactate dehydrogenase (LDH) release in H₂O₂-stimulated H9c2 cells. More importantly, donor 5e exhibited a potent cardioprotective effect in an in vivo myocardial infarction (MI) mouse model by reducing myocardial infarct size and cardiomyocyte apoptosis. Taken together, our studies demonstrated that these new allyl thioesters are potential cardioprotective agents by releasing H₂S.