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

Abstract

The present study established thirteen novel 8-hydroxyquinoline/chalcone hybrids3a-mof hopeful anticancer activity. According to NCI screening and MTT assay results, compounds3d-3f, 3i,3k,and3ldisplayed potent growth inhibition on HCT116 and MCF7 cells compared to Staurosporine. Among these compounds,3eand3fshowed outstanding superior activity against HCT116 and MCF7 cells and better safety toward normal WI-38 cells than Staurosporine. The enzymatic assay revealed that3e,3d, and3ihad goodtubulin polymerization inhibition (IC₅₀ = 5.3, 8.6, and 8.05 µM, respectively) compared to the reference Combretastatin A4 (IC₅₀ = 2.15 µM). Moreover,3e,3l, and3fexhibited EGFR inhibition (IC₅₀ = 0.097, 0.154, and 0.334 µM, respectively) compared to Erlotinib (IC₅₀ = 0.056 µM). Compounds3eand3fwere investigated for their effects on the cell cycle, apoptosis induction, andwnt1/β-cateningene suppression. The apoptosis markers Bax, Bcl2, Casp3, Casp9, PARP1, and β-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, Compounds3eand3fare promising antiproliferative leads with tubulin polymerization and EGFR kinase inhibition.

Keywords: 8-Hydroxyquinoline; Antiproliferative; Chalcone; Dual acting antiproliferative; EGFR kinase inhibitors; Tubulin Polymerization inhibition.