Targeting Highly Reactive Oxygen Species (hROS) for Prodrug Activation through a Cascade Reaction with Kinetic Tunability (CReKT) to Effect Linker Cleavage

Most ROS-sensitive cleavable linkers rely on their broad reactivity toward all ROS. However, individual ROS have very specialized functions in various pathologies. For example, HOCl/OCl^- is primarily produced in response to infection and/or inflammation by certain immune cells that express myeloperoxidase (MPO). We herein describe a novel HOCl/OCl^--selective prodrug approach through an oxidation-initiated Cascade Reaction with Kinetic Tunability (CReKT) for drug release. Specifically, HOCl/OCl^- oxidation of a phenylthioether is used to trigger prodrug activation via enhancing the nucleophilicity of the S-connected carbon for condensation-based payload release. The reactivity of the S-connected carbon is further augmented by tethering to an electron-withdrawing group (EWG) and by creating synergy with proximity effects. Tunability of release kinetics can be achieved by varying the EWG, substitution on the phenyl ring, and entropic factors. This approach offers new tools and sets a new direction in designing species-selective ROS-sensitive prodrugs.