Discovery of SIRT1-Activating Hydrogen Sulfide Donating Derivatives for Efficient Resistant of Myocardial Ischemic Injury,Journal of Medicinal Chemistry

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Discovery of SIRT1-Activating Hydrogen Sulfide Donating Derivatives for Efficient Resistant of Myocardial Ischemic Injury
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-09-13 , DOI: 10.1021/acs.jmedchem.4c01649
Shenglin Wang _{1,

2} , Dongyan Feng _{1,

2} , Weirenbo Wang _{1,

2} , Chao Zheng _{3,

4,

5} , Chaowei Liang _{1,

2} , Siqing Li ₆ , Haonan Li _{1,

2} , Fanxing Xu ₆ , Hao Cao ₇ , Huiming Hua _{1,

2} , Maosheng Cheng _{1,

8} , Dahong Li _{1,

2}

Affiliation

Activating SIRT1 or promoting SIRT1 expression are both protective against myocardial ischemia. Combining these approaches would be an effective strategy for treating ischemic heart disease. Herein, we identified lead compounds with SIRT1 activation activity through screening the natural product library, and five series of H₂S donating derivatives were designed and synthesized. Among them, compound 17 exerted an effective cardioprotective effect in vitro and in vivo. The addition of H₂S scavenger attenuated the protective activity, emphasizing the critical involvement of H₂S in the myocardial ischemia process. Interestingly, 17 exhibited stronger direct SIRT1 activative ability and induced higher SIRT1 expression capability compared to the lead. Furthermore, 17 attenuates oxidative stress-induced cardiomyocytes apoptosis by activating the SIRT1-PGC1α signaling pathway. Our study validated the promising potential of activating SIRT1 and promoting SIRT1 expression through H₂S to improve cardiomyocytes function, providing novel insights into the protective mechanisms during the progression of ischemic heart disease.

中文翻译：

发现 SIRT1 激活硫化氢供体衍生物有效抵抗心肌缺血性损伤

激活 SIRT1 或促进 SIRT1 表达都对心肌缺血具有保护作用。结合这些方法将是治疗缺血性心脏病的有效策略。在此，我们通过筛选天然产物库鉴定了具有 SIRT1 激活活性的先导化合物，并设计并合成了 5 个系列的 H₂S 供体衍生物。其中，化合物 17 在体外和体内均发挥了有效的心脏保护作用。添加 H₂S 清除剂减弱了保护活性，强调了 H₂S 在心肌缺血过程中的关键参与。有趣的是，与先导蛋白相比，17 个表现出更强的直接 SIRT1 激活能力，并诱导更高的 SIRT1 表达能力。此外，17 通过激活 SIRT1-PGC1α 信号通路减弱氧化应激诱导的心肌细胞凋亡。我们的研究验证了激活 SIRT1 并通过 H₂S 促进 SIRT1 表达以改善心肌细胞功能的潜力，为缺血性心脏病进展过程中的保护机制提供了新的见解。

更新日期：2024-09-13

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