A Persulfide Donor Responsive to Reactive Oxygen Species: Insights into Reactivity and Therapeutic Potential

Persulfides (R–SSH) have been hypothesized as critical components in sulfur-mediated redox cycles and as potential signaling compounds, similar to hydrogen sulfide (H2S). Hindering the study of persulfides is a lack of persulfide donor compounds with selective triggers that release discrete persulfide species. Herein we report the synthesis and characterization of an ROS-responsive, self-immolative persulfide donor. The donor, termed BDP-NAC, showed selectivity towards H2O2 over other potential oxidative or nucleophilic triggers, resulting in the sustained release of the persulfide of N-acetyl cysteine (NAC) over the course of 2 h, as measured by LCMS. Exposure of H9C2 cardiomyocytes to H2O2 revealed that BDP-NAC mitigated the effects of a highly oxidative environment in a dose-dependent manner over relevant controls and to a greater degree than common H2S donors sodium sulfide (Na2S) and GYY4137. BDP-NAC also rescued cells more effectively than a non-persulfide releasing control compound with a Bpin moiety in concert with common H2S donors and thiols.