Department of Chemistry, Johns Hopkins University, Baltimore, Maryland 21218, United States.
Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States.
J Am Chem Soc. 2020 Mar 4;142(9):4309-4316. doi: 10.1021/jacs.9b12180. Epub 2020 Feb 25.
The recent discovery of hydropersulfides (RSSH) in mammalian systems suggests their potential roles in cell signaling. However, the exploration of RSSH biological significance is challenging due to their instability under physiological conditions. Herein, we report the preparation, RSSH-releasing properties, and cytoprotective nature of alkylamine-substituted perthiocarbamates. Triggered by a base-sensitive, self-immolative moiety, these precursors show efficient RSSH release and also demonstrate the ability to generate carbonyl sulfide (COS) in the presence of thiols. Using this dually reactive alkylamine-substituted perthiocarbamate platform, the generation of both RSSH and COS is tunable with respect to half-life, pH, and availability of thiols. Importantly, these precursors exhibit cytoprotective effects against hydrogen peroxide-mediated toxicity in H9c2 cells and cardioprotective effects against myocardial ischemic/reperfusion injury, indicating their potential application as new RSSH- and/or COS-releasing therapeutics.
最近在哺乳动物系统中发现了氢过硫化物（RSSH），这表明它们在细胞信号转导中具有潜在的作用。然而，由于 RSSH 在生理条件下不稳定，因此探索 RSSH 的生物学意义具有挑战性。本文报道了烷基胺取代的硫代氨基甲酸酯的制备、RSSH 释放特性和细胞保护性质。这些前体通过对碱敏感的自耗蚀部分触发，表现出有效的 RSSH 释放，并在存在巯基的情况下表现出生成羰基硫（COS）的能力。利用这种双重反应性的烷基胺取代的硫代氨基甲酸酯平台，可以根据半衰期、pH 值和巯基的可用性来调节 RSSH 和 COS 的生成。重要的是，这些前体在 H9c2 细胞中对过氧化氢介导的毒性具有细胞保护作用，并对心肌缺血/再灌注损伤具有心脏保护作用，表明它们有潜力作为新的 RSSH-和/或 COS 释放治疗药物。
