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

Weijie Gu; Yuxuan Dai; Hao Qiang; Wei Shi; Chen Liao; Fangnuo Zhao; Wenlong Huang; Hai Qian

doi:10.1016/j.bioorg.2017.04.001

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

Bioorg Chem. 2017 Jun:72:116-122. doi: 10.1016/j.bioorg.2017.04.001. Epub 2017 Apr 8.

Authors

Weijie Gu¹, Yuxuan Dai¹, Hao Qiang¹, Wei Shi¹, Chen Liao¹, Fangnuo Zhao¹, Wenlong Huang², Hai Qian³

Affiliations

¹ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
² Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: ydhuangwenlong@126.com.
³ Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China. Electronic address: qianhai24@163.com.

PMID: 28411406
DOI: 10.1016/j.bioorg.2017.04.001

Abstract

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 0.11μM and 0.19μM 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.

Keywords: 2-Substituted-4-(2-fluorophenoxy) pyridine; Pyrazolone; Triazole; VEGFR-2; c-Met.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Line
Cell Proliferation / drug effects
Dose-Response Relationship, Drug
Drug Discovery
Human Umbilical Vein Endothelial Cells / drug effects
Humans
Models, Molecular
Molecular Structure
Protein Kinase Inhibitors / chemical synthesis
Protein Kinase Inhibitors / chemistry
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-met / antagonists & inhibitors*
Proto-Oncogene Proteins c-met / metabolism
Pyrazolones / chemistry
Pyrazolones / pharmacology*
Pyridines / chemical synthesis
Pyridines / chemistry
Pyridines / pharmacology*
Structure-Activity Relationship
Triazoles / chemistry
Triazoles / pharmacology*
Vascular Endothelial Growth Factor Receptor-2 / antagonists & inhibitors*
Vascular Endothelial Growth Factor Receptor-2 / metabolism

Substances

Protein Kinase Inhibitors
Pyrazolones
Pyridines
Triazoles
pyrazolone
Proto-Oncogene Proteins c-met
Vascular Endothelial Growth Factor Receptor-2