Antiproliferative effect, cell cycle arrest and apoptosis generation of novel synthesized anticancer heterocyclic derivatives based 4H-benzo[h]chromene.

• Design of novel fused chromene and pyrimidine derivatives as promising anticancer agents. • The cytotoxic activity of the new molecules was explored against three cancer cell lines MCF-7, HCT-116, and HepG-2. • Flow cytometric analyses also confirmed that some of the new compounds can induce apoptosis in MCF-7, HCT-116 and HepG-2 cell lines. • These compounds have significantly inhibited the invasion and migration of the different tested cancer cells. Novel β -enaminonitrile/ester compounds (4 , 6) and an imidate of 4 (9) were utilized as key scaffolds for the synthesis of newly 2-substituted 4 H -benzo[ h ]chromene (7, 8, 10, 11, 13, 14) and 7 H -benzo[ h ]chromeno[2,3– d ]pyrimidine derivatives (15 – 19). The spectral data confirmed the successful isolation of the desired compounds. The targeted compounds were assessed for their in vitro anticancer activity against mammary gland breast cancer cell line (MCF-7), human colon cancer (HCT-116), and liver cancer (HepG-2), while doxorubicin, vinblastine, and colchicine were utilized as standard references drugs. Some of the examined compounds displayed high growth inhibitory activity against the three different cell lines. For example, the aminoimino derivative (18) exhibited excellent antitumor activity versus all cancer cell lines with IC 50 values = 0.45 µg/mL, 0.7 µg/mL, and 1.7 µg/mL. Among the tested molecules, compounds 9 , 15 , and 18 were selected for further study regarding their effects on cell cycle analysis, apoptosis assay, caspase 3/7 activity, and DNA fragmentation. We found that these three potent cytotoxic compounds induce cell cycle arrest at the S and G2/M phases, which causes apoptosis. Furthermore, these compounds significantly inhibit the invasion and migration of the different tested cancer cells. Finally, the SAR survey highlighted the antitumor activity of the new molecules that was remarkably influenced by the hydrophilicity of substituent as well the fused rings at certain positions. [ABSTRACT FROM AUTHOR]