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Eur J Med Chem. 2017 Sep 29;138:1076-1088. doi: 10.1016/j.ejmech.2017.07.011. Epub 2017 Jul 8.

Discovery of 5,6-diaryl-1,2,4-triazines hybrids as potential apoptosis inducers.

Author information

1
New Drug Research & Development Center, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, China; Key Laboratory of Technology of Drug Preparation, Zhengzhou University, Ministry of Education, China; Key Laboratory of Henan Province for Drug Quality and Evaluation, China.
2
Pathology and Laboratory Medicine, University of California, Irvine, Orange, CA 92868, USA.
3
School of Basic Medical Sciences, Zhengzhou University, Zhengzhou 450001, China. Electronic address: celeron16@163.com.
4
New Drug Research & Development Center, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, China; Key Laboratory of Technology of Drug Preparation, Zhengzhou University, Ministry of Education, China; Key Laboratory of Henan Province for Drug Quality and Evaluation, China. Electronic address: zhangyb@zzu.edu.cn.
5
New Drug Research & Development Center, School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China; Collaborative Innovation Center of New Drug Research and Safety Evaluation, Henan Province, China; Key Laboratory of Technology of Drug Preparation, Zhengzhou University, Ministry of Education, China; Key Laboratory of Henan Province for Drug Quality and Evaluation, China. Electronic address: liuhm@zzu.edu.cn.

Abstract

A series of 5,6-diaryl-1,2,4-triazines hybrids bearing a 1,2,3-triazole linker were synthesized by molecular hybridization strategy and evaluated for antiproliferative activity against three selected cancer cell lines (MGC-803, EC-109 and PC-3). The first structure-activity relationship (SAR) for these 5,6-diaryl-1,2,4-triazines is explored in this report with evaluation of 15 variants of the structural class. Among these chemical derivatives, 3-(((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)thio)-5,6-diphenyl-1,2,4-triazine (11E) showed the more potent inhibitory effect against three cell lines than 5-Fu. Cellular mechanism studies in MGC-803 cells elucidated 11E inhibited colony formation and arrested cell cycle at G2/M phase. Furthermore, compound 11E caused morphological changes, decreased mitochondrial membrane potential, and induced apoptosis through the apoptosis-related proteins in MGC-803 cells. It was the first time, to our knowledge, that 5,6-diaryl-1,2,4-triazines bearing a 1,2,3-triazole linker were used as potential apoptosis inducers.

KEYWORDS:

5,6-Diaryl-1,2,4-triazines; Apoptosis; Apoptosis-related proteins; Molecular hybridization strategy; Morphological changes

PMID:
28763643
PMCID:
PMC5975277
DOI:
10.1016/j.ejmech.2017.07.011
[Indexed for MEDLINE]
Free PMC Article

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