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Structure-based discovery of novel 4-(2-fluorophenoxy)quinoline derivatives as c-Met inhibitors using isocyanide-involved multicomponent reactions
- Source :
- European Journal of Medicinal Chemistry. 193:112241
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- The c-Met kinase has emerged as a promising target for the development of small molecule antitumor agents because of its close relationship with the progression of many human cancers, poor clinical outcomes and even drug resistance. In this study, two novel series of 6,7-disubstitued-4-(2-fluorophenoxy)quinoline derivatives containing α-acyloxycarboxamide or α-acylaminoamide scaffolds were designed, synthesized, and evaluated for their in vitro biological activities against c-Met kinase and four cancer cell lines (H460, HT-29, MKN-45, and MDA-MB-231). Most of the target compounds exhibited moderate to significant potency and possessed selectivity for H460 and HT-29 cancer cell lines. The preliminary structure-activity relationships indicated that α-acyloxycarboxamide or α-acylaminoamide as 5-atom linker contributed to the antitumor potency. Among these compounds, compound 10m (c-Met IC50 = 2.43 nM, a multitarget tyrosine kinase inhibitor) exhibited the most potent inhibitory activities against H460, HT-29 and MDA-MB-231 cell lines with IC50 of 0.14 ± 0.03 μM, 0.20 ± 0.02 μM and 0.42 ± 0.03 μM, which were 1.7-, 1.3- and 1.6-fold more active than foretinib, respectively. In addition, concentration-dependent assay and time-dependent assay indicated compound 10m can inhibit the proliferation of H460 cell in a time and concentration dependent manner. Moreover, docking studies revealed the common mode of interaction with the c-Met binding site, suggesting that 10m is a potential candidate for cancer therapy deserving further study.
- Subjects :
- Time Factors
C-Met
medicine.drug_class
Antineoplastic Agents
01 natural sciences
Tyrosine-kinase inhibitor
Structure-Activity Relationship
03 medical and health sciences
chemistry.chemical_compound
Cell Line, Tumor
Drug Discovery
medicine
Humans
Protein Kinase Inhibitors
IC50
Cell Proliferation
030304 developmental biology
Pharmacology
0303 health sciences
Cyanides
Dose-Response Relationship, Drug
Molecular Structure
010405 organic chemistry
Kinase
Organic Chemistry
Quinoline
Foretinib
General Medicine
Proto-Oncogene Proteins c-met
Small molecule
0104 chemical sciences
Molecular Docking Simulation
chemistry
Biochemistry
Docking (molecular)
Quinolines
Drug Screening Assays, Antitumor
Subjects
Details
- ISSN :
- 02235234
- Volume :
- 193
- Database :
- OpenAIRE
- Journal :
- European Journal of Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....11667afa7a449d1f00cac007ee98d550