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- Title
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.
- Authors
Abdelall, Eman K. A.; Elshemy, Heba A. H.; Labib, Madlen B.; Mohamed, Fatma E. A.
- Abstract
New 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.
- Subjects
CELL cycle; CANCER cells; HEPATOCELLULAR carcinoma; BINDING sites; APOPTOSIS; BAX protein
- Publication
Drug Development Research, 2024, Vol 85, Issue 1, p1
- ISSN
0272-4391
- Publication type
Article
- DOI
10.1002/ddr.22133