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

作　　者：Guorui Li Yi Yang Yaya Zhang Peiling Huang Jiangyu Yan Zhibin Song Quan Yuan Jing Huang 

机构地区：[1]Institute of Chemical Biology and Nanomedicine(ICBN),State Key Laboratory of Chemo/Biosensing and Chemometrics,College of Biology,College of Chemistry and Chemical Engineering,Hunan Provincial Key Laboratory of Biomacromolecular Chemical Biology,Hunan University,Changsha 410082 [2]Key Laboratory of Functional Small Organic Molecules,Ministry of Education,College of Chemistry and Chemical Engineering,Jiangxi Normal University,Nanchang 330022

出　　处：《CCS Chemistry》2022年第5期1654-1670,共17页中国化学会会刊（英文）

基　　金：funded by the National Natural Science Foundation of China(nos.31871365 and 21708007);the Technology Innovation Program of Hunan Province(no.2018RS3060).

摘　　要：“Off-target effect”is one of the obstacles for targeted prodrugs in chemotherapy.To circumvent this issue,herein we propose a dual biomarker cascadeactivated 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,CQB 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.

关 键 词：PRODRUG cascade activated ROS TYR MELANOMA mitochondria redox homeostasis THERANOSTICS 

分 类 号：R739.5[医药卫生—肿瘤]