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European journal of medicinal chemistry v.143, 2018년, pp.1968 - 1980   SCI SCIE
본 등재정보는 저널의 등재정보를 참고하여 보여주는 베타서비스로 정확한 논문의 등재여부는 등재기관에 확인하시기 바랍니다.

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

Lan, Junjie (State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 3491 Baijin Road, Guiyang 550014, PR China ) ; Huang, Lan (State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 3491 Baijin Road, Guiyang 550014, PR China ) ; Lou, Huayong (State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 3491 Baijin Road, Guiyang 550014, PR China ) ; Chen, Chao (State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 3491 Baijin Road, Guiyang 550014, PR China ) ; Liu, Tangjingjun (State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 3491 Baijin Road, Guiyang 550014, PR China ) ; Hu, Shengcao (The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Sciences, 3491 Baijin Road, Guiyang, 550014, PR China ) ; Yao, Yao (State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 3491 Baijin Road, Guiya ) ; Song, Junrong ; Luo, Jun ; Liu, Yazhou ; Xia, Bin ; Xia, Lei ; Zeng, Xueyi ; Ben-David, Yaacov ; Pan, Weidong ;
  • 초록  

    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 IC 50 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. Highlights Novel C 14 -urea-tetrandrine and C 14 -thiourea-tetrandrine derivatives with antitumor activities were designed. The introduction of urea or thiourea unit increases antitumor activity. Compound 4g showed the strongest anti-PC3 activity and induction of tumor cell apoptosis by caspase intrinsic pathway. Graphical abstract [DISPLAY OMISSION]


  • 주제어

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

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