Design, synthesis of novel chromene‐based scaffolds targeting hepatocellular carcinoma: Cell cycle arrest, cytotoxic effect against resistant cancer cells, apoptosis induction, and c‐Src inhibition

AbstractNew chromene derivatives were synthesized based on 4‐(3,4‐dimethoxy)‐4H‐chromene scaffold. All target compounds exhibited cytotoxic activity against HepG2 cells (IC50 = 2.40–141.22 μM). Chromens 5 and 9 showed superior cytotoxicity over staurosporine (IC50 = 18.27 μM) and vinblastine (IC50 = 5.20 μM). c‐Src kinase inhibition assay of compounds 5 and 9 displayed the dominant c‐Src inhibitory activity of 5 (IC50 = 0.184 μM) over 9 (IC50 = 0.288 μM). The safety of the most potent compound 5 against normal WI‐38 cells was confirmed via its IC50 of 115.75 μM comparable with 5‐FU (IC50 = 16.28 μM). Moreover, the promising chromene 5 displayed potent cytotoxicity against resistant HepG2 cells with IC50 of 26.03 μM comparable with 5‐FU (IC50 = 42.68 μM). The most active chromene 5 arrested the HepG2 cell cycle at the S phase and induced a 29‐fold increase in the total number of apoptotic cells indicating pre‐G1 apoptosis. The ability of compound 5 to induce apoptosis was supported via elevation of caspase‐3, caspase‐7, caspase‐9 and proapoptotic Bax protein levels in addition to downregulation of the antiapoptotic Bcl2 protein. Molecular docking studies of compound 5 showed good binding interaction pattern inside c‐Src kinase enzyme active site.