2. Academic Validation
  3. Design and synthesis of novel C14-urea-tetrandrine derivatives with potent anti-cancer activity

Design and synthesis of novel C14-urea-tetrandrine derivatives with potent anti-cancer activity

  • Eur J Med Chem. 2018 Jan 1:143:1968-1980. doi: 10.1016/j.ejmech.2017.11.007.
Junjie Lan 1,  Lan Huang 2,  Huayong Lou 1,  Chao Chen 1,  Tangjingjun Liu 1,  Shengcao Hu 3,  Yao Yao 1,  Junrong Song 4,  Jun Luo 5,  Yazhou Liu 1,  Bin Xia 1,  Lei Xia 1,  Xueyi Zeng 1,  Yaacov Ben-David 6,  Weidong Pan 7
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, PR China.
  • 2 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 3491 Baijin Road, Guiyang 550014, PR China.
  • 3 The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, 3491 Baijin Road, Guiyang, 550014, PR China; Zunyi Medical University, 6 West Road, Zunyi 563000, PR China.
  • 4 The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, 3491 Baijin Road, Guiyang, 550014, PR China; Guizhou University, Huaxi Avenue South, Guiyang 550025, PR China.
  • 5 The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, 3491 Baijin Road, Guiyang, 550014, PR China; Guiyang College of Traditional Chinese Medicine, 50 East Road, Guiyang 550002, PR China.
  • 6 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, PR China. Electronic address: yaacovbendavid@hotmail.com.
  • 7 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, PR China. Electronic address: wdpan@163.com.
PMID: 29133049 DOI: 10.1016/j.ejmech.2017.11.007
Abstract

Tetrandrine is a dibenzyltetrahydroisoquinoline alkaloid, isolated from traditional Chinese medicinal plant Stephania tetrandra, with anti-tumor activity. Our previous study identified several derivatives of tetrandrine showing better activities than parental compound against human hepatocellular carcinoma cells. To increase diversity and cytotoxic activities of the original compound, a series of novel 14-urea-tetrandrine derivatives were synthesized through structural modification of tetrandrine. These derivaties demonstrated a moderate to strong anti-proliferative activities against human cell lines HEL and K562 (Leukemia), prostate (PC3), breast (MDA-MB-231) and melanoma (WM9). Compound 4g showed strongest cytotoxic effect against PC3 cells with IC50 value of 0.64 μM, which was 12-fold, 31-fold and 26-fold lower than the parental tetrandrine, 5-fluorouracil and cisplatin, respectively. Preliminary structure-activity relationship study indicated that urea subsititution was the key pharmacophore for the enhancement of their antitumor activities. Induction of apoprosis by 4g was associated with the activation of pro-apoptotic protein Bax and inhibition of antiapoptosis proteins Survivin as well as Bcl-2. Moreover, activation of caspases led to increase cleavage of PARP, which further accelerates apoptotic cell death. These results reveal that the compound 4g may be used as a potential Anticancer drug candidate.

Keywords

Anticancer activity; Apoptosis; Caspase; PARP; Tetrandrine derivatives; Urea.

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