Design, synthesis, cytotoxic activities, and molecular docking of chalcone hybrids bearing 8-hydroxyquinoline moiety with dual tubulin/EGFR kinase inhibition

The present study established thirteen novel 8-hydroxyquinoline/chalcone hybrids 3a-m of hopeful anticancer activity. According to NCI screening and MTT assay results, compounds 3d-3f, 3i, 3k, and 3l displayed potent growth inhibition on HCT116 and MCF7 cells compared to Staurosporine. Among these com-pounds, 3e and 3f showed outstanding superior activity against HCT116 and MCF7 cells and better safety toward normal WI-38 cells than Staurosporine. The enzymatic assay revealed that 3e, 3d, and 3i had good tubulin polymerization inhibition (IC50 = 5.3, 8.6, and 8.05 mu M, respectively) compared to the reference Combretastatin A4 (IC50 = 2.15 mu M). Moreover, 3e, 3l, and 3f exhibited EGFR inhibition (IC50 = 0.097, 0.154, and 0.334 mu M, respectively) compared to Erlotinib (IC50 = 0.056 mu M). Compounds 3e and 3f were investigated for their effects on the cell cycle, apoptosis induction, and wnt1/8-catenin gene suppression. The apoptosis markers Bax, Bcl2, Casp3, Casp9, PARP1, and 8-actin were detected by Western blot. In-silico molecular docking, physicochemical, and pharmacokinetic studies were implemented for the validation of dual mechanisms and other bioavailability standards. Hence, Compounds 3e and 3f are promising antiproliferative leads with tubulin polymerization and EGFR kinase inhibition.

Automated summary

This study successfully synthesized thirteen novel 8-hydroxyquinoline/chalcone hybrids, compounds 3a-m, which showed promising anticancer activity. Among these compounds, 3e and 3f exhibited superior activity against cancer cells and better safety towards normal cells compared to Staurosporine. Furthermore, compounds 3e, 3d, and 3i demonstrated good inhibition of tubulin polymerization and compounds 3e, 3l, and 3f showed EGFR inhibition. These compounds also showed potential effects on cell cycle, apoptosis induction, and gene suppression. In-silico molecular docking and other studies validated their dual mechanisms and bioavailability standards.