A Reactive Oxygen Species-Tyrosinase Cascade-Activated Prodrug for Selectively Suppressing Melanoma

"Off-target effect" is one of the obstacles for targeted prodrugs in chemotherapy. To circumvent this issue, herein we propose a dual biomarker cascade-activated prodrug strategy based on high levels of reactive oxygen species (ROS) and tyrosinase (TYR) in melanoma cells. A representative prodrug, Coumarin-Quinazolinone-phenylBoronic acid pinacol ester (CQB), was prepared. The prodrug contained Coumarin-Quinazolinone (CQ) as mitochondria targeting and monitoring moiety and phenylboronic acid pinacol ester as a cascade-activated prowarhead. After activation by the endogenous ROS and subsequent TYR in melanoma cells, COB can be converted to the final active reagent Coumarin-Quinazolinone-o-Quinone (CQQ) that contains o-quinone group as the reactive species. CQQ may interact with cellular nucleophiles to exert its genotoxic effect and disrupt the cellular redox balance. This enables CQB to selectively suppress melanoma. CQB accumulates in the mitochondria and causes mitochondrial dysfunction via affecting mitochondrial DNA integrity. This cascade-activated prodrug may provide a precise strategy for melanoma theranostics. [GRAPHICS] .