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

Persulfides (RSSH) have been hypothesized as critical components in sulfur‐mediated redox cycles and as potential signaling compounds, similar to hydrogen sulfide (H 2 S). Hindering the study of persulfides is a lack of persulfide‐donor compounds with selective triggers that release discrete persulfide species. Reported here is the synthesis and characterization of a ROS‐responsive (ROS=reactive oxygen species), self‐immolative persulfide donor. The donor, termed BDP‐NAC, showed selectivity towards H 2 O 2 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 H 2 O 2 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 H 2 S donors sodium sulfide (Na 2 S) and GYY4137. BDP‐NAC also rescued cells more effectively than a non‐persulfide‐releasing control compound in concert with common H 2 S donors and thiols.