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A series of 1H-benzo[f]chromene moieties (4a–z) were synthesised under Ultrasonic irradiation and confirmed with spectral analyses. Derivative 4i solely possessed an X-ray single crystal. The anti-proliferative efficacy of the desired molecules has been explored against three cancer cells: MCF-7, HCT-116, and HepG-2 with the cytotoxically active derivatives screened against MCF-7/ADR and normal cells HFL-1 and WI-38. Furthermore, compounds 4b–d, 4k, 4n, 4q, and 4w, which possessed good potency against MCF-7/ADR, were tested as permeability glycoprotein (P-glycoprotein [P-gp]) expression inhibitors. The attained data confirmed that 4b–d, 4q, and 4w exhibited strong expression inhibition against the P-gp alongside its cytotoxic effect on MCF-7/ADR. The western blot results and Rho123 accumulation assays showed that compounds 4b–d, 4q, and 4w effectively inhibited the P-gp expression and efflux function. Meanwhile, 4b–d, 4q, and 4w induced apoptosis and accumulation of the treated MCF-7/ADR cells in the G1 phase and 4k and 4n in the S phase of the cell cycle. [ABSTRACT FROM AUTHOR]

Abstract This work presents the combined microwave assisted synthesis, spectroscopic analyses, cytotoxic effects, and molecular docking studies of the chromene fused ring systems with various substituents of the terminal halogenated phenyl ring derivatives of 6-methoxy-4 H -benzo [ h ]chromene (4a-m). The structures of the synthesized compounds were established on the basis of their spectral data, IR, 1H NMR, 13C NMR, 13C NMR-DEPT, and MS data. The target compounds were evaluated for their antitumor activities against three cancer cell lines: MCF-7, HCT-116, and HepG-2, in comparison to Vinblastine and Colchicine as reference drugs with the usage of a MTT colorimetric assay. The most active compounds were subjected to further mechanistic analysis through the assay of the c-Src Kinase inhibition activity. The SAR studies reported that the substitution at the 4-position of the 2-amino-4 H -benzo [ h ]chromene nucleus with specific halogen atoms and lipophilic characters increased the ability of the molecule against the different cell lines. The Molecular Operating Environment (MOE) was used to evaluate the interactions between the ligand and the c-Src Kinase enzyme. Compound 4m , having the 3,5-dibromo-2-methoxyphenyl group attached to the 4 H -benzo [ h ]chromene moiety at the 4-postion, exhibited a promising interaction with the c-Src Kinase, which leads to a strong inhibition of this enzyme. Graphical abstract Image 1 Highlights • A novel series of halogenated derivatives of 6-methoxy-4 H -benzo [ h ]chromene. • The assessment of the antitumor activities against three cancer cell lines. • The c-Src Kinase inhibition activity. • The role of halogen atoms at position 4. [ABSTRACT FROM AUTHOR]

• 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]