2. Academic Validation
  3. Design and synthesis of novel tetrandrine derivatives as potential anti-tumor agents against human hepatocellular carcinoma

Design and synthesis of novel tetrandrine derivatives as potential anti-tumor agents against human hepatocellular carcinoma

  • Eur J Med Chem. 2017 Feb 15:127:554-566. doi: 10.1016/j.ejmech.2017.01.008.
Junjie Lan 1,  Ning Wang 2,  Lan Huang 3,  Yazhou Liu 3,  Xiaopan Ma 3,  Huayong Lou 3,  Chao Chen 3,  Yibin Feng 4,  Weidong Pan 5
Affiliations

Affiliations

  • 1 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 3491 Baijin Road, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, 3491 Baijin Road, Guiyang 550014, China; College of Pharmacy Guizhou University, Huaxi Avenue South, Guiyang 550025, China.
  • 2 School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam 999077, Hong Kong.
  • 3 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 3491 Baijin Road, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, 3491 Baijin Road, Guiyang 550014, China.
  • 4 School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, 10 Sassoon Road, Pokfulam 999077, Hong Kong. Electronic address: yfeng@hku.hk.
  • 5 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 3491 Baijin Road, Guiyang 550014, PR China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, 3491 Baijin Road, Guiyang 550014, China. Electronic address: wdpan@163.com.
PMID: 28109948 DOI: 10.1016/j.ejmech.2017.01.008
Abstract

Tetrandrine, a lead anti-tumor compound with a bis-benzyltetrahydroisoquinoline skeleton isolated from medicinal plant Stephania tetrandra. In order to obtain active anti-tumor agents and evaluate their structure-activity relationships, a series of novel tetrandrine derivatives were designed and synthesized in this study. Their anti-tumor activities against human hepatocellular carcinoma cell lines (HMCC97L and PLC/PRF/5) were also evaluated. The bioassay results showed that the derivatives exhibited moderate to strong inhibition against the two cell lines. Among them, compound 31 showed prominent cytotoxicity with IC50 = 1.06 μM (15.8 folds than that of tetrandrine, and 30.3 folds than that of Sorafenib). Further studies on the mechanisms demonstrated that the in vitro anti-tumor activity of compound 31 was predominantly due to the inducement of Apoptosis of HCC cells. Compound 31 was capable of initiating endoplasmic reticulum stress-associated apoptotic cell death, and the activation of JNK as well as Caspase pathways were probably involved. Our results suggest that compound 31, a new 14-position substituted amide tetrandrine derivative, might be a potential candidate for developing novel anti-HCC drugs in the coming future.

Keywords

Apoptosis; ER stress; Hepatocellular carcinoma; JNK; Tetrandrine.

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