2. Academic Validation
  3. Using gene expression database to uncover biology functions of 1,4-disubstituted 1,2,3-triazole analogues synthesized via a copper (I)-catalyzed reaction

Using gene expression database to uncover biology functions of 1,4-disubstituted 1,2,3-triazole analogues synthesized via a copper (I)-catalyzed reaction

  • Eur J Med Chem. 2017 May 26:132:90-107. doi: 10.1016/j.ejmech.2017.03.034.
Chun-Li Su 1,  Chia-Ling Tseng 2,  Chintakunta Ramesh 3,  Hsiao-Sheng Liu 4,  Chi-Ying F Huang 5,  Ching-Fa Yao 6
Affiliations

Affiliations

  • 1 Department of Human Development and Family Studies, National Taiwan Normal University, Taipei 106, Taiwan. Electronic address: chunlisu@ntnu.edu.tw.
  • 2 Department of Human Development and Family Studies, National Taiwan Normal University, Taipei 106, Taiwan.
  • 3 Department of Chemistry, National Taiwan Normal University, Taipei 116, Taiwan.
  • 4 Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan; Center of Infectious Disease and Signaling Research Center, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan.
  • 5 Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan; Department of Biochemistry, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address: cyhuang5@ym.edu.tw.
  • 6 Department of Chemistry, National Taiwan Normal University, Taipei 116, Taiwan. Electronic address: cheyaocf@ntnu.edu.tw.
PMID: 28342400 DOI: 10.1016/j.ejmech.2017.03.034
Abstract

We have synthesized bioactive 1,4-disubstituted 1,2,3-triazole analogues containing 2H-1,4-benzoxazin-3-(4H)-one derivatives via 1,3-dipolar cycloaddition in the presence of CuI. All the reactions proceeded smoothly and afforded its desired products in excellent yields. Among these analogues, 3y exhibited a better cytotoxic effect on human hepatocellular carcinoma (HCC) Hep 3B cells and displayed less cytotoxicity on normal human umbilical vein endothelial cells, compared with Sorafenib, a targeted therapy for advanced HCC. 3y also induced stronger Apoptosis and Autophagy. Addition of curcumin enhanced 3y-induced cytotoxicity by further induction of Autophagy. Using gene expression signatures of 3y to query Connectivity Map, a glycogen synthase kinase-3 inhibitor (AR-A014418) was predicted to display similar molecular action of 3y. Experiments further demonstrate that AR-A014418 acted like 3y, and vice versa. Overall, our data suggest the chemotherapeutic potential of 3y on HCC.

Keywords

1,4-Disubstituted 1,2,3-triazole analogues; Apoptosis; Autophagy; Connectivity map; L1000 gene expression profiling; Sorafenib.

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