An Innovative Hydrogen Peroxide-Sensing Scaffold and Insights Towards its Potential as an ROS-Activated Persulfide Donor

Reactive sulfur species, such as hydrogen sulfide, persulfides, and polysulfides, have recently emerged as key signaling molecules and important physiological mediators within mammalian systems. To further assess the therapeutic potential of their exogenous administration, we report on the development of a unique hydrogen peroxide (H2O2)-sensing motif and its capacity for providing cellular protection against oxidative stress while serving as a reactive oxygen species (ROS)-activated persulfide donor. With the strategic implementation of a gem-dimethyl group that promotes both cyclization and stability, we found the initial rate of payload release from this newly derived scaffold to be directly proportional to the concentration of H2O2 and to proceed via an unprecedented pathway that avoids the production of electrophilic byproducts, a severe limitation that has plagued the physiological application of previous designs.