A series of new β-carboline derivatives containing an imidazolium moiety were designed and synthesized via the reaction of β-carboline-1-carboxaldehydes, acetyl chloride, primary amine, and formaldehyde. The antitumor activity of the synthesized compounds was examined against lung carcinoma (A549), gastric carcinoma (BGC-823), murine colon carcinoma (CT-26), liver carcinoma (Bel-7402) and breast carcinoma (MCF-7) cells. The results indicated that most compounds exhibited significant antiproliferative activity, in some cases greater than that of cisplatin, and compound 3z was found to be the most potent antiproliferative agent against A549, BGC823, CT-26, Bel-7402 and MCF-7 cell lines with an IC50 value of 2.7 ± 0.4, 2.7 ± 0.6, 2.4 ± 0.2, 3.2 ± 0.2, and 5.6 ± 0.3 μM, respectively. Combined with favorable in vitro potency, the antitumor efficacies of the selected compounds in mice were also evaluated. Compound 3z exhibited potent antitumor activity with a tumor inhibition rate of 48.6% in sarcoma 180 models. Preliminary investigations on the mechanisms of action revealed that compound 3z could dramatically inhibit EA.hy926 cell tube formation in a dose-dependent manner. Further investigation of the preliminary mechanism of action demonstrated that compound 3z had obvious angiogenesis inhibitory effects in the chicken chorioallantoic membrane (CAM) assay. The results of the docking study showed a good fitting of the new compounds 3o and 3z to the active site of VEGFR-2 with a docking score energy of -11.31 kcal per mole and -11.26 kcal per mole, respectively.
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