A Reactive Oxygen Species-Tyrosinase Cascade-Activated Prodrug for Selectively Suppressing Melanoma
A Reactive Oxygen Species-Tyrosinase Cascade-Activated Prodrug for Selectively Suppressing Melanoma
复制标题
一种活性氧-酪氨酸酶级联激活的前药，用于选择性抑制黑色素瘤
DOI：
10.31635/ccschem.021.202101032
复制
发表时间：
2022-01-01
期刊：
影响因子：
11.2
通讯作者：
Huang, Jing
中科院分区：
文献类型：
--
作者：
Li, Guorui;Yang, Yi;Huang, Jing
“脱靶效应”是靶向前药在化疗中应用的障碍之一。为了解决这个问题，本文中我们提出了一种基于黑色素瘤细胞中高水平的活性氧（ROS）和酪氨酸酶（TYR）的双生物标志物级联激活的前药策略。制备代表性前药香豆素-喹唑啉酮-苯基硼酸频哪醇酯（CQB）。前药含有香豆素喹唑啉酮（CQ）作为线粒体靶向和监测部分，苯基硼酸频哪醇酯作为级联激活的前弹头。在黑色素瘤细胞中，COB被内源性ROS和随后的TYR激活后，可以转化为最终的活性试剂香豆素-喹唑啉酮-邻醌（CQQ），其含有邻醌基团作为反应物种。CQQ可能与细胞亲核试剂相互作用，发挥其遗传毒性作用，破坏细胞氧化还原平衡。这使得CQB能够选择性地抑制黑色素瘤。CQB在线粒体中积累并通过影响线粒体DNA完整性而引起线粒体功能障碍。这种级联激活的前药可能为黑色素瘤治疗诊断提供精确的策略。[图形]。
"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].