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- Title
Design, Synthesis and Biological Evaluation of Novel α‐Acyloxycarboxamide‐Based Derivatives as c‐Met Inhibitors.
- Authors
Feng, Yu‐juan Please confirm that given names (blue) and surnames/family names (vermilion) have been identified correctly. -->; Ren, Yu‐Lin; Zhao, Li‐Ming; Xue, Guo‐Qiang; Yu, Wen‐Hao; Yang, Jia‐Qi; Liu, Jun‐Wei
- Abstract
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 α‐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 α‐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 μmol/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.
- Subjects
BIOSYNTHESIS; QUINOLINE derivatives; TREATMENT effectiveness; CELL cycle; CELL lines
- Publication
Chinese Journal of Chemistry, 2021, Vol 39, Issue 8, p2241
- ISSN
1001-604X
- Publication type
Article
- DOI
10.1002/cjoc.202100106