Using gene expression database to uncover biology functions of 1,4-disubstituted 1,2,3-triazole analogues synthesized via a copper (I)-catalyzed reaction.
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.
Department of Human Development and Family Studies, National Taiwan Normal University, Taipei 106, Taiwan. Electronic address: chunlisu@ntnu.edu.tw.
Chun-Li
CL
Su
Department of Human Development and Family Studies, National Taiwan Normal University, Taipei 106, Taiwan.
Chia-Ling
CL
Tseng
Department of Chemistry, National Taiwan Normal University, Taipei 116, Taiwan.
Chintakunta
C
Ramesh
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.
Hsiao-Sheng
HS
Liu
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.
Chi-Ying F
CF
Huang
Department of Chemistry, National Taiwan Normal University, Taipei 116, Taiwan. Electronic address: cheyaocf@ntnu.edu.tw.
Ching-Fa
CF
Yao
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001343:Autophagy / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D003300:Copper / Q000737:chemistry; D003474:Curcumin / Q000737:chemistry / Q000494:pharmacology; D030541:Databases, Genetic; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy; D013329:Structure-Activity Relationship; D013844:Thiazoles; D014230:Triazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives
D000970:Antineoplastic Agents; D013844:Thiazoles; D014230:Triazoles; D003300:Copper; C479831:N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea; D014508:Urea; D038362:Glycogen Synthase Kinase 3; D003474:Curcumin
1,4-Disubstituted 1,2,3-triazole analogues; Apoptosis; Autophagy; Connectivity map; L1000 gene expression profiling; Sorafenib