Journal
CHINESE JOURNAL OF CHEMISTRY
Volume 39, Issue 8, Pages 2241-2250Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cjoc.202100106
Keywords
4-(2-Fluorophenoxy)quinoline derivatives; c-Met inhibitors; Passerini reaction; alpha-Acyloxycarboxamide; Biological evaluation
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Funding
- Fundamental Research Funds for the Central Universities [31920170193, 31920200026]
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The study identified compound 25s as a promising lead compound with potent antiproliferative activities against multiple cancer cell lines, inducing apoptosis in A549 cells and inhibiting c-Met phosphorylation. This compound showed potential for further development as an anticancer drug.
Main observation and conclusion Dysregulated HGF/c-Met signalling has been associated with many human cancers, poor clinical outcomes, and even resistance acquisition to some approved targeted therapies. As such, c-Met kinase has emerged as an attractive target for anticancer drug discovery. Herein, a series of 6,7-disubstitued-4-(2-fluorophenoxy)quinoline derivatives bearing alpha-acyloxycarboxamide moiety were designed, synthesized via Passerini reaction as the key step, and evaluated for their in vitro biological activities against c-Met kinase and five selected cancer cell lines. The preliminary structure-activity relationship demonstrated that alpha-acyloxycarboxamide as the 5-atom linker maintained the potent antitumor potency. Among these compounds, compound 25s (c-Met IC50 = 4.06 nmol/L) was identified as the most promising lead compound and displayed the most potent antiproliferative activities against A549, HT-29 and MDA-MB-231 cell lines with IC50 of 0.39, 0.20, and 0.58 mu mol/L, which were 1.3-, 1.4- and 1.2-fold superior to foretinib, respectively. The further studies indicated that compound 25s can induce apoptosis of A549 cells and arrest efficiently the cell cycle distribution in G2/M phase of A549 cells. Moreover, compound 25s can also inhibit c-Met phosphorylation in A549 cells by a dose-dependent manner. Collectively, these results indicated that compound 25s could be a potential anticancer lead compound deserving for further development. [GRAPHICS] .
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