Synthesis and biological evaluation of panaxatriol derivatives against myocardial ischemia/reperfusion injury in the rat

  • Eur J Med Chem. 2020 Jan 1;185:111729. doi: 10.1016/j.ejmech.2019.111729.
Qiong Wu  1 ,  Ruiying Wang  2 ,  Yang Shi  1 ,  Wenchao Li  1 ,  Meng Li  3 ,  Peng Chen  1 ,  Bowen Pan  1 ,  Qing Wang  1 ,  Caifeng Li  4 ,  Jianbing Wang  5 ,  Guibo Sun  2 ,  Xiaobo Sun  2 ,  Hongzheng Fu  6
Affiliations
  • 1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Science, Peking University, Beijing, 100191, PR China.
  • 2. Beijing Key Laboratory of Innovative Drug Discovery of Traditional Chinese Medicine (Natural Medicine) and Translational Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100193, PR China.
  • 3. Department of Chemistry, University of Warwick, Coventry, CV4 7AL, United Kingdom.
  • 4. College of Traditional Chinese Medicine, Shenyang Pharmaceutical University, Shenyang, 110016, PR China.
  • 5. Guangdong-Macau Traditional Chinese Medicine Technology Industrial Park Development Co., Ltd, Zhuhai, 519000, PR China.
  • 6. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Science, Peking University, Beijing, 100191, PR China. Electronic address: [email protected].
PMID: 31655431 DOI: 10.1016/j.ejmech.2019.111729
Abstract

Panaxatriol (PT) is a natural product derived from ginseng that possesses cardioprotective effects in isolated rat hearts. To develop more potent therapeutic agents against myocardial ischemia/reperfusion (MI/R) injury from natural products, a novel series of heterocycle ring-fused panaxatriol derivatives were designed and synthesized. In vitro results showed that approximately half of them exhibited increased cytoprotective activity compared with PT in a cardiomyocyte model of oxygen-glucose deprivation and reperfusion (OGD/R) injury. Furthermore, the in vitro activity of the representative derivative, compound 18, was also confirmed in a rat model of MI/R injury. In vivo results showed that 18 can markedly reduce myocardial infarction size, decrease circulating cardiac troponin I (cTnI) leakage, and alleviate cardiac tissue damage in the rats. Therefore, these findings provide the basis for further development of novel anti-MI/R injury agents.

Keywords
Heterocyclic compounds; Ischemia/reperfusion injury; Panaxatriol; Structure-activity relationships; Synthesis.
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