Design, synthesis and molecular docking studies of some novel spiro[indoline-3, 4′-piperidine]-2-ones as potential c-Met inhibitors

Deregulation of receptor tyrosine kinase c-Met has been reported in human cancers and is considered as an attractive target for small molecule drug discovery. In this study, a series of spiro[indoline-3, 4′-piperidine]-2-ones were designed, synthesized and evaluated as novel c-Met inhibitors. The re...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2012-04, Vol.50, p.370-375
Main Authors: Ye, Lianbao, Tian, Yuanxin, Li, Zhonghuang, Jin, Hong, Zhu, Zhengguang, Wan, Shanhe, Zhang, Junyan, Yu, Pengjiu, Zhang, Jiajie, Wu, Shuguang
Format: Article
Language:English
Subjects:
Antineoplastic agents
Binding Sites
Biological and medical sciences
Blotting, Western
c-Met inhibitor
Cell Proliferation - drug effects
Drug Design
Drug Discovery
Fluorescence Resonance Energy Transfer
General aspects
Humans
Inhibitory Concentration 50
Medical sciences
Models, Molecular
Molecular docking
Molecular Structure
Pharmacology. Drug treatments
Piperidines - chemistry
Protein Kinase Inhibitors - chemical synthesis
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins c-met - antagonists & inhibitors
Spiro[indoline-3, 4′-piperidine]-2-ones
Stomach Neoplasms - drug therapy
Stomach Neoplasms - metabolism
Structure-Activity Relationship
Suzuki coupling reaction
Tumor Cells, Cultured
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Summary:Deregulation of receptor tyrosine kinase c-Met has been reported in human cancers and is considered as an attractive target for small molecule drug discovery. In this study, a series of spiro[indoline-3, 4′-piperidine]-2-ones were designed, synthesized and evaluated as novel c-Met inhibitors. The results showed that the majority of the compounds exhibited significant inhibitory effect on c-Met with IC50 values of 0.0147–17 μM in TR-FRET-based assay and IC50 values of 1.56–1400 μM in cell-based assay. Furthermore, our docking experiments verified the results and explained the molecular mechanism of eminent activities to c-Met. [Display omitted] ► We design and synthesize some novel spiro[indoline-3, 4′-piperidine]-2-ones. ► We investigate their inhibitory effect on c-Met with biological assay. ► Biological assay IC50 values are 0.0147–17 μM and cell IC50 values are 1.56–1400 μM. ► We explain molecular mechanism of eminent activities to c-Met by molecular docking.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2012.02.016