Background: The Hepatocyte Growth Factor Receptor (HGFR) c-Met is over-expressed and/or
mutated in various human tumor types. Dysregulation of c-Met/HGF signaling pathway affects cell proliferation,
survival and motility, leading to tumor growth, angiogenesis, and metastasis. Therefore, c-Met has become
an attractive target for cancer therapy.
Objective: This study is aimed to evaluate a new series of 4-phenoxypyridine derivatives containing semicarbazones
moiety for its cytotoxicity.
Methods: A series of novel 4-phenoxypyridines containing semicarbazone moieties were synthesized and
evaluated for their in vitro cytotoxic activities against MKN45 and A549 cancer cell lines and some selected
compounds were further examined for their inhibitory activity against c-Met kinase. In order to evaluate the
mechanism of cytotoxic activity of compound 24, cell cycle analysis, Annexin V/PI staining assay, AO/EB
assay, wound-healing assay and docking analysis with c-Met were performed.
Results: The results indicated that most of the compounds showed moderate to good antitumor activity. The
compound 28 showed well cytotoxic activity against MKN45 and A549 cell lines with IC50 values of 0.25μM
and 0.67μM, respectively. Compound 24 showed good activity on c-Met and its IC50 value was 0.093μM.
Conclusion: Their preliminary Structure-Activity Relationships (SARs) studies indicated that electronwithdrawing
groups on the terminal phenyl rings are beneficial for improving the antitumor activity. Treatments
of MKN45 cells with compound 24 resulted in cell cycle arrest in G2/M phase and induced apoptosis in a
dose-dependent manner. In addition, AO/EB assays indicated 24 induced dose-dependent apoptosis of A549
and MKN45 cells. Wound-healing assay results indicated that compound 24 strongly inhibited A549 cell