2. Academic Validation
  3. Design and synthesis of novel SCM-198 analogs as cardioprotective agents: Structure-activity relationship studies and biological evaluations

Design and synthesis of novel SCM-198 analogs as cardioprotective agents: Structure-activity relationship studies and biological evaluations

  • Eur J Med Chem. 2020 Aug 15:200:112469. doi: 10.1016/j.ejmech.2020.112469.
Shanshan Luo 1,  Shengtao Xu 2,  Junkai Liu 2,  Fenfen Ma 3,  Yi Zhun Zhu 4
Affiliations

Affiliations

  • 1 Key Laboratory of Cardiovascular and Cerebrovascular Medicine, Nanjing Medical University, 101 Longmian Avenue, Nanjing, 211166, PR China; Pharmacy and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, PR China; Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 200032, PR China.
  • 2 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing, 210009, PR China.
  • 3 Department of Pharmacy, Shanghai Pudong Hospital, Fudan University, Shanghai, 201399, PR China.
  • 4 Pharmacy and State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, PR China; Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 200032, PR China. Electronic address: yzzhu@must.edu.mo.
PMID: 32485530 DOI: 10.1016/j.ejmech.2020.112469
Abstract

SCM-198 (Leonurine) has attracted great attention due to its cardioprotective effects in myocardial infarction (MI). However, no systematic modifications and structure-activity relationship (SAR) studies could be traced so far. In this study, 35 analogs of SCM-198 were designed, synthesized and their cardioprotective effects were evaluated. The cell viability assay on cardiomyocyte cell line H9c2 challenged with H2O2 showed that several analogs exhibited more potent cytoprotective effects than SCM-198 at 1 μM and 10 μM concentrations. LDH release level in cells treated with 1 μM 14o was comparable with cells treated with 10 μM SCM-198. Results of Bcl-2 expression and Caspase-3 activation accordingly indicated higher protective activity of 14o than SCM-198. Moreover, in a mouse model of MI, the mice pretreated with 14o had much lower infarct size compared with that of SCM-198. The mechanism study suggested that 14o improved cardiac morphology and reduced Apoptosis of cardiomyocytes in the border zone of infarction, as proved by H&E and TUNEL staining.

Keywords

Cardioprotection; Leonurine; Myocardial infarction; SCM-198; Structural modification.

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