生物正交化学
化学
前药
部分
炔丙基
体内
组合化学
劈理(地质)
生物化学
点击化学
立体化学
催化作用
生物
工程类
生物技术
岩土工程
断裂(地质)
作者
Tao Sun,Tian Lv,Jianbing Wu,Mingchao Zhu,Yue Fei,Jie Zhu,Yihua Zhang,Zhangjian Huang
标识
DOI:10.1021/acs.jmedchem.0c01435
摘要
Bioorthogonal decaging reactions for controllable drug activation within complex biological systems are highly desirable yet extremely challenging. Herein, we find a new class of Pt(II)-triggered bioorthogonal cleavage reactions in which Pt(II) but not Pt(IV) complexes effectively trigger the cleavage of O/N-propargyl in a variety of ranges of caged molecules under biocompatible conditions. Based on these findings, we propose a general strategy for integrated bioorthogonal prodrugs and accordingly design a prodrug 16, in which a Pt(IV) moiety is covalently connected with an O2-propargyl diazeniumdiolate moiety. It is found that 16 can be specifically reduced by cytoplasmic reductants in human ovarian cancer cells to liberate cisplatin, which subsequently stimulates the cleavage of O2-propargyl to release large amounts of NO in situ, thus generating synergistic and potent tumor suppression activity in vivo. Therefore, Pt(II)-triggered depropargylation and the integration concept might provide a general strategy for broad applicability of bioorthogonal cleavage chemistry in vivo.
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