Hydrogen Sulfide Donors Activated by Reactive Oxygen Species

Hydrogen sulfide (H 2 S) exhibits promising protective effects in many (patho)physiological processes, as evidenced by recent reports using synthetic H 2 S donors in different biological models. Herein, we report the design and evaluation of compounds denoted PeroxyTCM, which are the first class of reactive oxygen species (ROS)‐triggered H 2 S donors. These donors are engineered to release carbonyl sulfide (COS) upon activation, which is quickly hydrolyzed to H 2 S by the ubiquitous enzyme carbonic anhydrase (CA). The donors are stable in aqueous solution and do not release H 2 S until triggered by ROS, such as hydrogen peroxide (H 2 O 2 ), superoxide (O 2 − ), and peroxynitrite (ONOO − ). We demonstrate ROS‐triggered H 2 S donation in live cells and also demonstrate that PeroxyTCM‐1 provides protection against H 2 O 2 ‐induced oxidative damage, suggesting potential future applications of PeroxyTCM and similar scaffolds in H 2 S‐related therapies.