Discovery of SIRT1-Activating Hydrogen Sulfide Donating Derivatives for Efficient Resistant of Myocardial Ischemic Injury

被引：1

作者：

Wang, Shenglin ^{[1
,2
]}

Feng, Dongyan ^{[1
,2
]}

Wang, Weirenbo ^{[1
,2
]}

Zheng, Chao ^{[3
,5
,6
]}

Liang, Chaowei ^{[1
,2
]}

Li, Siqing ^{[4
]}

Li, Haonan ^{[1
,2
]}

Xu, Fanxing ^{[4
]}

Cao, Hao ^{[7
,8
]}

Hua, Huiming ^{[1
,2
]}

Cheng, Maosheng ^{[1
,9
]}

Li, Dahong ^{[1
,2
]}

机构：

[1] Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Peoples R China

[2] Shenyang Pharmaceut Univ, Sch Tradit Chinese Mat Med, Shenyang 110016, Peoples R China

[3] Ctr Addict & Mental Hlth CAMH, Campbell Family Mental Hlth Res Inst, Azrieli Ctr Neuroradiochemistry, Brain Hlth Imaging Ctr, Toronto, ON M5T 1R8, Canada

[4] Shenyang Pharmaceut Univ, Wuya Coll Innovat, Shenyang 110016, Peoples R China

[5] Univ Toronto, Dept Psychiat, Toronto, ON M5T 1R8, Canada

[6] Univ Toronto, Dept Pharmacol & Toxicol, Toronto, ON M5T 1R8, Canada

[7] Shenyang Pharmaceut Univ, Sch Life Sci & Biopharmaceut, Shenyang 110016, Liaoning, Peoples R China

[8] Shenyang Pharmaceut Univ, Key Lab Microbial Pharmaceut, Shenyang 110016, Liaoning, Peoples R China

[9] Shenyang Pharmaceut Univ, Sch Pharmaceut Engn, Shenyang 110016, Peoples R China

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2024年 / 67卷 / 19期

基金：

中国国家自然科学基金;

关键词：

HEART-DISEASE; GLOBAL BURDEN; H2S DONORS; PROTECTS; APOPTOSIS; MITOCHONDRIA; METABOLISM; INFARCTION; REGULATOR;

D O I：

10.1021/acs.jmedchem.4c01649

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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-PGC1 alpha 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.

引用

页码：17657 / 17675

页数：19