Discovery of β‑Carboline Derivatives as a Highly Potent Cardioprotectant against Myocardial Ischemia-Reperfusion Injury

Timely myocardial reperfusion salvages ischemic myocardium from infarction, whereas reperfusion itself induces cardiomyocyte death, which is called myocardial ischemia/reperfusion (MI/R) injury. Herein, β-carboline derivative 17c was designed and synthesized with obvious myocardial protective activi...

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Published in:Journal of medicinal chemistry 2021-07, Vol.64 (13), p.9166-9181
Main Authors: Zhang, Hong, Zhang, Rong-Hong, Liao, Xiang-Ming, Yang, Dan, Wang, Yu-Chan, Zhao, Yong-Long, Xu, Guo-Bo, Liu, Chun-Hua, Li, Yong-Jun, Liao, Shang-Gao, Zhou, Meng
Format: Article
Language:English
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Summary:Timely myocardial reperfusion salvages ischemic myocardium from infarction, whereas reperfusion itself induces cardiomyocyte death, which is called myocardial ischemia/reperfusion (MI/R) injury. Herein, β-carboline derivative 17c was designed and synthesized with obvious myocardial protective activity for the first time. Pretreatment of 17c effectively protected the cardiomyocyte H9c2 cells from H2O2-induced lactate dehydrogenase leakage and restored the endogenous antioxidants, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Besides, 17c effectively protected the mitochondria through decreasing the reactive oxygen species overproduction and enhancing the mitochondrial membrane potential. As a result, 17c significantly reduced the necrosis of cardiomyocytes in H2O2-induced oxidative stress, which was more potent than polydatin. In MI/R injury rats, 17c pretreatment obviously increased the levels of SOD and GSH-Px and inhibited the apoptosis of cardiomyocytes. Through this way, the size of myocardial infarction was significantly reduced after MI/R injury in vivo, better than that of polydatin, suggesting that 17c is a promising cardioprotectant for the prevention of MI/R injury.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.1c00384