2. Academic Validation
  3. Discovery of SIRT1-Activating Hydrogen Sulfide Donating Derivatives for Efficient Resistant of Myocardial Ischemic Injury

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

  • J Med Chem. 2024 Oct 10;67(19):17657-17675. doi: 10.1021/acs.jmedchem.4c01649.
Shenglin Wang 1 2,  Dongyan Feng 1 2,  Weirenbo Wang 1 2,  Chao Zheng 3 4 5,  Chaowei Liang 1 2,  Siqing Li 6,  Haonan Li 1 2,  Fanxing Xu 6,  Hao Cao 7,  Huiming Hua 1 2,  Maosheng Cheng 1 8,  Dahong Li 1 2
Affiliations

Affiliations

  • 1 Key Laboratory of Structure-Based Drug Design & Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, P. R. China.
  • 2 School of Traditional Chinese Materia Medica, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, P. R. China.
  • 3 Azrieli Centre for Neuro-Radiochemistry, Brain Health Imaging Centre, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON M5T 1R8, Canada.
  • 4 Department of Psychiatry, University of Toronto, Toronto, ON M5T-1R8, Canada.
  • 5 Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5T-1R8, Canada.
  • 6 Wuya College of Innovation, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, P. R. China.
  • 7 School of Life Science and Biopharmaceutics, and Key Laboratory of Microbial Pharmaceutics, Liaoning Province, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, P. R. China.
  • 8 School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, P. R. China.
PMID: 39268676 DOI: 10.1021/acs.jmedchem.4c01649
Abstract

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-PGC1α 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.

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