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

Because of the association of various pathological conditions with the over-production of reactive oxygen species (ROS), there is a strong interest in ROS-sensitive linker chemistry for drug delivery and other applications. Most ROS-sensitive cleavable linkers rely on their broad reactivity toward all ROS including the least reactive ROS, hydrogen peroxide, and highly reactive oxygen species (hROS) such as hypochlorite, peroxynitrite, and hydroxy radical. However, individual ROS has very specialized functions and unique roles in various pathologies. Therefore, there is a need for species-selective activation chemistry for drug delivery applications. OCl- is the second most abundant ROS and primarily produced in response to infection and/or inflammation by certain immune cells that express myeloperoxidase (MPO). We herein describe a novel hROS-selective prodrug approach through a OCl--initiated Cascade Reaction with Kinetic Tunability (CReKT) for drug release. Specifically, ClO- oxidation of a phenylthioether is used to create a cleavable event, 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 has four key features: (1) stable prodrugs, (2) selectivity for hypochlorite-activation, (3) tunability in release kinetics, and (4) free of labile metal- or boron-based groups. This approach affords new tools and sets a new direction in designing species-selective ROS-sensitive prodrugs.