Discovery of novel 2-substituted-4-(2-fluorophenoxy) pyridine derivatives possessing pyrazolone and triazole moieties as dual c-Met/VEGFR-2 receptor tyrosine kinase inhibitors

被引：35

作者：

Gu, Weijie ^{[1
]}

Dai, Yuxuan ^{[1
]}

Qiang, Hao ^{[1
]}

Shi, Wei ^{[1
]}

Liao, Chen ^{[1
]}

Zhao, Fangnuo ^{[1
]}

Huang, Wenlong ^{[1
,2
]}

Qian, Hai ^{[1
,2
]}

机构：

[1] China Pharmaceut Univ, Ctr Drug Discovery, State Key Lab Nat Med, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, Peoples R China

[2] China Pharmaceut Univ, Jiangsu Key Lab Drug Discovery Metab Dis, 24 Tongjiaxiang, Nanjing 210009, Jiangsu, Peoples R China

来源：

BIOORGANIC CHEMISTRY | 2017年 / 72卷

基金：

中国国家自然科学基金;

关键词：

c-Met; VEGFR-2; 2-Substituted-4-(2-fluorophenoxy) pyridine; Pyrazolone; Triazole; ENDOTHELIAL GROWTH-FACTOR; C-MET; CANCER; ANGIOGENESIS; EXPRESSION; PROTEIN; DESIGN; VEGF; METASTASIS; RELAPSE;

D O I：

10.1016/j.bioorg.2017.04.001

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

In our efforts to develop novel dual c-Met/VEGFR-2 inhibitors as potential anticancer agents, a series of 2-substituted-4-(2-fluorophenoxy) pyridine derivatives bearing pyrazolone scaffold were designed and synthesized. The cell proliferation assay in vitro demonstrated that most target compounds had inhibition potency on both c-Met and VEGFR-2, especially compound 9h, 12b and 12d. Based on the further enzyme assay in vitro, compound 12d was considered as the most promising one, the IC50 values of which were 0.11 mu M and 0.19 mu M for c-Met and VEGFR-2, respectively. Further molecular docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, indicating that 12d was a potential compound for cancer therapy deserving further study. (C) 2017 Elsevier Inc. All rights reserved.

引用

页码：116 / 122

页数：7

共 33 条

[1] Role of tyrosine kinase inhibitors in cancer therapy [J].