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.