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

Abstract

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.

• Authors: Hong Zhang, Rong-Hong Zhang, Xiang-Ming Liao, Dan Yang, Yu-Chan Wang, Yong-Long Zhao, Guo-Bo Xu, Chun-Hua Liu, Yong-Jun Li, Shang-Gao Liao, Meng Zhou
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 64 Issue 13 Pg. 9166-9181 (07 08 2021) ISSN: 1520-4804 [Electronic] United States
• PMID: 34132541 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Carbolines
• Protective Agents
• norharman
• Hydrogen Peroxide
• Glutathione Peroxidase
• Superoxide Dismutase

Topics

• Animals
• Carbolines (pharmacology)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Drug Discovery
• Glutathione Peroxidase (metabolism)
• Hydrogen Peroxide (antagonists & inhibitors, pharmacology)
• Male
• Molecular Structure
• Myocardial Reperfusion Injury (chemically induced, drug therapy, metabolism)
• Oxidative Stress (drug effects)
• Protective Agents (pharmacology)
• Rats
• Rats, Sprague-Dawley
• Structure-Activity Relationship
• Superoxide Dismutase (metabolism)