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  2. Structure-based discovery of novel 4-(2-fluorophenoxy)quinoline derivatives as c-Met inhibitors using isocyanide-involved multicomponent reactions

Structure-based discovery of novel 4-(2-fluorophenoxy)quinoline derivatives as c-Met inhibitors using isocyanide-involved multicomponent reactions

  • Eur J Med Chem. 2020 May 1;193:112241. doi: 10.1016/j.ejmech.2020.112241.
Xiang Nan 1 Hui-Jing Li 2 Sen-Biao Fang 3 Qin-Ying Li 4 Yan-Chao Wu 5
Affiliations

Affiliations

  • 1 School of Marine Science and Technology, Harbin Institute of Technology, Weihai, 264209, PR China.
  • 2 School of Marine Science and Technology, Harbin Institute of Technology, Weihai, 264209, PR China; Weihai Institute of Marine Biomedical Industrial Technology, Wendeng District, Weihai, 264400, PR China. Electronic address: lihuijing@iccas.ac.cn.
  • 3 School of Computer Science and Engineering, Central South University, Changsha, 410082, PR China. Electronic address: fangsb@csu.edu.cn.
  • 4 School of Marine Science and Technology, Harbin Institute of Technology, Weihai, 264209, PR China; Weihai Institute of Marine Biomedical Industrial Technology, Wendeng District, Weihai, 264400, PR China.
  • 5 School of Marine Science and Technology, Harbin Institute of Technology, Weihai, 264209, PR China; Weihai Institute of Marine Biomedical Industrial Technology, Wendeng District, Weihai, 264400, PR China. Electronic address: ycwu@iccas.ac.cn.
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.

Keywords

4-(2-fluorophenoxy)quinoline derivatives; Biological evaluation; Docking study; Isocyanide-involved multicomponent reactions; c-Met inhibitors.

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