Design, synthesis, and screening of ortho-amino thiophene carboxamide derivatives on hepatocellular carcinomaas VEGFR-2Inhibitors.

AbstractIn this work, design, synthesis, and screening of thiophene carboxamides 4–13 and 16–23 as dual vascular endothelial growth factor receptors (VEGFRs) and mitotic inhibitors was reported. All compounds were screened against two gastrointestinal solid cancer cells, HepG-2 and HCT-116 cell lines. The most active cytotoxic derivatives 5 and 21 displayed 2.3- and 1.7-fold higher cytotoxicity than Sorafenib against HepG-2 cells. Cell cycle and apoptosis analyses for compounds 5 and 21 showed cells accumulation in the sub-G1 phase, and cell cycle arrest at G2/M phase. The apoptotic inducing activities of compounds 5 and 21were correlated to the elevation of p53, increase in Bax/Bcl-2 ratio, and increase in caspase-3/7.Compounds 5 and 21 showed potent inhibition againstVEGFR-2 (IC50 = 0.59 and 1.29 μM) and β-tubulin polymerization (73% and 86% inhibition at their IC50 values).Molecular docking was performed with VEGFR-2 and tubulin binding sites to explain the displayed inhibitory activities.