2. Academic Validation
  3. Semisynthesis and biological evaluation of (+)-sclerotiorin derivatives as antitumor agents for the treatment of hepatocellular carcinoma

Semisynthesis and biological evaluation of (+)-sclerotiorin derivatives as antitumor agents for the treatment of hepatocellular carcinoma

  • Eur J Med Chem. 2022 Mar 15;232:114166. doi: 10.1016/j.ejmech.2022.114166.
Yang Hai 1,  Jia-Jia Geng 1,  Peng-Jie Li 1,  Wei-Ping Ma 1,  Cui-Fang Wang 1,  Mei-Yan Wei 2,  Xue-Mei Hou 1,  Guang-Ying Chen 3,  Yu-Cheng Gu 4,  Ming Liu 5,  Chang-Lun Shao 6
Affiliations

Affiliations

  • 1 Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, People's Republic of China.
  • 2 Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, People's Republic of China; College of Food Science and Engineering, Ocean University of China, Qingdao, 266003, People's Republic of China. Electronic address: mywei95@126.com.
  • 3 Key Laboratory of Tropical Medicinal Resource Chemistry of Ministry of Education, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou, 571158, People's Republic of China.
  • 4 Syngenta Jealott's Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom.
  • 5 Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, People's Republic of China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266200, People's Republic of China. Electronic address: lmouc@ouc.edu.cn.
  • 6 Key Laboratory of Marine Drugs, The Ministry of Education of China, School of Medicine and Pharmacy, Ocean University of China, Qingdao, 266003, People's Republic of China; Laboratory for Marine Drugs and Bioproducts, Qingdao National Laboratory for Marine Science and Technology, Qingdao, 266200, People's Republic of China. Electronic address: shaochanglun@163.com.
PMID: 35152092 DOI: 10.1016/j.ejmech.2022.114166
Abstract

Hepatocellular carcinoma is one of the most common primary hepatic malignancy. Herein, a series of semisynthesized derivatives (2-30) of the natural product (+)-sclerotiorin (1) was prepared and evaluated the cytotoxic activities against six Cancer cell lines. Among them, 3 and 5 were the most effective compounds against human hepatocellular carcinoma Bel-7402 cell line with IC50 values of 1.45 and 1.15 μM, respectively. Molecular mechanism study showed that 5 disrupted the mitochondrial membrane potential and induced Apoptosis in a caspase-dependent manner. In addition, 5 affected Akt and ERK signaling pathways and induced Akt and ERK proteins degradation through ubiquitin-proteasome system. Furthermore, 5 displayed significant in vivo Anticancer effects in the xenograft models with decreasing the tumor mass by 52.5%. The safety evaluation was confirmed by acute toxicity subchronic toxicity tests, paraffin sections of mice organ and blood routine examination. Taken together, 5 can be developed as a potential therapeutic agent for hepatocellular carcinoma.

Keywords

(+)-Sclerotiorin; AKT and ERK proteins; Antitumor; Hepatocellular carcinoma; Mouse xenograft model.

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