Controllable Hydrogen Sulfide Donors and Their Activity against Myocardial Ischemia-Reperfusion Injury

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• 作者：Yu Zhao ; Shashi Bhushan ; Chuntao Yang ; Hiroyuki Otsuka ; Jason D. Stein ; Armando Pacheco ; Bo Peng ; Nelmi O. Devarie-Baez ; Hector C. Aguilar ; David J. Lefer ; Ming Xian
• 刊名：ACS Chemical Biology
• 出版年：2013
• 出版时间：June 21, 2013
• 年：2013
• 卷：8
• 期：6
• 页码：1283-1290
• 全文大小：433K
• 年卷期：v.8,no.6(June 21, 2013)
• ISSN：1554-8937

文摘

Hydrogen sulfide (H₂S), known as an important cellular signaling molecule, plays critical roles in many physiological and/or pathological processes. Modulation of H₂S levels could have tremendous therapeutic value. However, the study on H₂S has been hindered due to the lack of controllable H₂S releasing agents that could mimic the slow and moderate H₂S release in vivo. In this work we report the design, synthesis, and biological evaluation of a new class of controllable H₂S donors. Twenty-five donors were prepared and tested. Their structures were based on a perthiol template, which was suggested to be involved in H₂S biosynthesis. H₂S release mechanism from these donors was studied and proved to be thiol-dependent. We also developed a series of cell-based assays to access their H₂S-related activities. H9c2 cardiac myocytes were used in these experiments. We tested lead donors鈥?cytotoxicity and confirmed their H₂S production in cells. Finally we demonstrated that selected donors showed potent protective effects in an in vivo murine model of myocardial ischemia-reperfusion injury, through a H₂S-related mechanism.