Abstract
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•β-enamionitriles, linked 8-bromo-1H-benzo[f]chromene moieties were synthesized as potential anticancer agents.•The cytotoxic activity was tested against (MCF-7), (HCT-116) and (HepG-2) cell lines.•Compounds 4b,d,e,i,k were able to induce cell cycle arrest at G2/M phase, increase the production of Caspases 3, 8, and 9, and finally cause intrinsic and extrinsic apoptotic cell death.•Compounds 4b,d,e,i,k prompting apoptotic cell death due to the dual inhibitory effect on the catalytic activity of topoisomerase II.
In our endeavors to develop novel and powerful agents with antiproliferative activities, a series of β-enamionitriles, linked to the 8-bromo-1H-benzo[f]chromene moieties (4a-m), was designed and synthesized under microwave irradiation conditions. The structures of the target compounds were established on the basis of their spectral data: IR, 1H NMR, 13C NMR, 13C NMR-DEPT/APT, 19F NMR and MS. Furthermore, the antiproliferative properties were evaluated against the human cancer cell lines MCF-7, HCT-116, and HepG-2 in comparison to the positive controls Vinblastine and Doxorubicin, employing the viability assay. The obtained results confirmed that most of the tested molecules revealed strong and selective cytotoxic activities against the three cancer cell lines. The most potent cytotoxic compounds 4b, 4d, 4e, 4i, and 4k were elected for further examination, such as the cell cycle analysis, the apoptosis assay, the Caspase production, and the DNA fragmentation. This study also revealed that the desired compounds stimulate cell cycle arrest at the G2/M phases, increase the production of Caspases 3, 8, and 9, and finally cause intrinsic and extrinsic apoptotic cell death. Moreover, these compounds suppress the action of the topoisomerase II enzyme and also disrupt the microtubule functions. The SAR study of the synthesized compounds verified that the substitution on the phenyl ring of the 1H-benzo[f]chromene nucleus, accompanied with the presence of the bromine atom at the 8-position, increases the ability of these molecules against different cell lines.