生物正交化学
化学
前药
组合化学
体内
试剂
动力学
连接器
点击化学
药物输送
白霉素类
生物化学
有机化学
抗真菌
卡斯波芬金
计算机科学
生物
操作系统
医学
物理
生物技术
两性霉素B
量子力学
皮肤病科
作者
Zhou Zhou,Shun Feng,Jain Zhou,Xingyue Ji,Ya‐Qiu Long
标识
DOI:10.1021/acs.jmedchem.1c01493
摘要
Although a myriad of bioorthogonal prodrugs have been developed, very few of them present both fast reaction kinetics and complete cleavage. Herein, we report a new bioorthogonal prodrug strategy with both fast reaction kinetics (k2: ∼103 M-1 s-1) and complete cleavage (>90% within minutes) using the bioorthogonal reaction pair of N-oxide and boron reagent. Distinctively, an innovative 1,6-elimination-based self-immolative linker is masked by N-oxide, which can be bioorthogonally demasked by a boron reagent for the release of both amino and hydroxy-containing payload in live cells. Such a strategy was applied to prepare a bioorthogonal prodrug for a camptothecin derivative, SN-38, resulting in 10-fold weakened cytotoxicity against A549 cells, 300-fold enhanced water solubility, and "on-demand" activation upon a click reaction both in vitro and in vivo. This novel bioorthogonal prodrug strategy presents significant advances over the existing ones and may find wide applications in drug delivery in the future.
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