Alkylamine-Substituted Perthiocarbamates: Dual Precursors to Hydropersulfide and Carbonyl Sulfide with Cardioprotective Actions
Alkylamine-Substituted Perthiocarbamates: Dual Precursors to Hydropersulfide and Carbonyl Sulfide with Cardioprotective Actions
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DOI：
10.1021/jacs.9b12180
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发表时间：
2020-03-04
影响因子：
15
通讯作者：
Toscano, John P.
中科院分区：
文献类型：
--
作者：
Khodade, Vinayak S.;Pharoah, Blaze M.;Toscano, John P.
最近在哺乳动物系统中发现的氢过硫化物（RSSH）表明它们在细胞信号传导中的潜在作用。然而，由于 RSSH 在生理条件下不稳定，探索其生物学意义具有挑战性。在此，我们报道了烷基胺取代的过硫代氨基甲酸酯的制备、RSSH 释放特性和细胞保护性质。这些前体由碱敏感的自焚部分触发，表现出有效的 RSSH 释放，并且还表现出在硫醇存在下生成羰基硫 (COS) 的能力。使用这种双反应性烷基胺取代的过硫代氨基甲酸酯平台，RSSH 和 COS 的生成可根据硫醇的半衰期、pH 值和可用性进行调节。重要的是，这些前体在 H9c2 细胞中表现出针对过氧化氢介导的毒性的细胞保护作用以及针对心肌缺血/再灌注损伤的心脏保护作用，表明它们作为新的 RSSH 和/或 COS 释放疗法的潜在应用。
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.