Synthesis and molecular docking studies of new furochromone derivatives as p38 MAPK inhibitors targeting human breast cancer MCF-7 cells.
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Based on the reported high expression of p38 MAP kinase in invasive breast cancers and the activity of different functionalized chromone derivatives as p38 inhibitors, a new set of 4,9-dimethoxy/4-methoxy-7-methyl-5-oxo-5H-furo[3,2-g]chromone derivatives were efficiently synthesized aiming to introduce new p38 MAP kinase suppressors as new anti-breast cancer tools. Using GOLD program, molecular docking study of the target compounds into p38 MAP kinase binding pocket was performed to highlight their scores, mode of binding and the important interactions to the amino acid residues of the enzyme. MTT assay investigated that fifteen target compounds produced marked cytotoxic potency higher than that obtained by Doxorubicin against MCF-7 cancer cells of IC50 values ranging from 0.007 to 0.17M vs IC50; 0.62M of doxorubicin. Eleven selected compounds were evaluated for their inhibitory potency against p38 MAPK kinase. The derivatives IVa, Va,b, VIa, IXb and XIIIa represented significant activity (IC50; 0.19-0.67M) comparing to the reference drug SB203580 (IC50; 0.50M). In virtue of its promising cytotoxic and p38 MAP kinase inhibition potency, the furochromone derivative IXb was selected as a representative example to investigate its mechanistic effects on cell cycle progression and induction of apoptosis in MCF-7 cell lines. The results showed that the compound IXb induced cell cycle cessation at G2/M phase preventing its mitotic cycle, alongside its noteworthy activation of caspases-9 and -3 which might mediate the apoptosis of MCF-7 cells.