Design and synthesis of novel 2-(4-(2-(dimethylamino)ethyl)-4H-1,2,4-triazol-3-yl)pyridines as potential antitumor agents

被引：31

作者：

Qin, Mingze ^{[1
]}

Zhai, Xin ^{[1
]}

Xie, Hongbo ^{[2
]}

Ma, Junjie ^{[1
]}

Lu, Kuan ^{[1
]}

Wang, Yu ^{[1
]}

Wang, Lihui ^{[3
]}

Gu, Yucheng ^{[4
]}

Gong, Ping ^{[1
]}

机构：

[1] Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang 110016, Peoples R China

[2] Harbin Med Univ, Coll Bioinformat Sci & Technol, Harbin 150081, Peoples R China

[3] Shenyang Pharmaceut Univ, Dept Pharmacol, Shenyang 110016, Peoples R China

[4] Syngenta, Jealotts Hill Int Res Ctr, Bracknell RG42 6EY, Berks, England

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 81卷

基金：

中国国家自然科学基金;

关键词：

Synthesis; 4-(2-(Dimethylamino)ethyl)-4H-1,2,4-triazole; Antitumor activity; BIOLOGICAL EVALUATION; SORAFENIB; RAF; DERIVATIVES; INHIBITOR; DISCOVERY; ANALOGS;

D O I：

10.1016/j.ejmech.2014.04.059

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

New 2-(4-(2-(dimethylamino)ethyl)-4H-1,2,4-triazol-3-yl)pyridine derivatives were synthesized and evaluated for their in vitro cytotoxicity against five cancer cell lines namely MKN-45, H460, HT-29, A549 and U87MG, as well as the normal cell line WI-38. Nearly all the compounds exhibited superior potency to sorafenib with a better selectivity towards the MKN-45, H460 and HT-29 cell lines. In addition, the enzymatic screening result demonstrated that the optimized compounds possessed potent Raf kinase inhibition as well as favorable enzyme selectivity. The most promising compound, 11f, showed high levels of cytotoxicity against MKN-45, H460 and HT-29 cells with IC50 values of 51, 72 and 130 nM, respectively, which are 45.5, 30.4 and 27.8 folds higher than the corresponding IC50 values for sorafenib against these cell lines. Structure activity relationships revealed that the dimethylaminoethyl group was crucial for high activity. (C) 2014 Elsevier Masson SAS. All rights reserved.

引用

页码：47 / 58

页数：12

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