ABSTRACT
This study deals with synthesis of a new set of benzofuran and 5H-furo[3,2-g]chromone linked various heterocyclic functionalities using concise synthetic approaches aiming to gain new antiproliferative candidates against MCF-7 breast cancer cells of p38α MAP kinase inhibiting activity. The biological data proved the significant sensitivity of breast cancer cell lines MCF-7 towards most of the prepared compounds in comparison with doxorubicin. In addition, compounds IIa,b, Va,b, VIa,b, VIIa,b, VIIIa,b, XIc showed significant in vitro p38α MAPK inhibiting potency comparable to the reference standard SB203580. Cell cycle analysis and apoptosis detection data demonstrated that compound VIa induced G2/M phase arrest and apoptosis in MCF-7 cancer cells, in addition to its activation of the caspases-9 and -3. Gold molecular docking studies rationalized the highly acceptable correlation between the calculated docking scores of fitness and the biological data of p38α MAP kinase inhibition. The newly prepared benzofuran and 5H-furo[3,2-g]chromone derivatives might be considered as new promising nuclei in anti-breast cancer chemotherapeutics for further functionalization, optimization and in-depth biological studies.
Subject(s)
Antineoplastic Agents/pharmacology , Benzofurans/pharmacology , Chromones/pharmacology , Mitogen-Activated Protein Kinase 14/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Apoptosis/drug effects , Benzofurans/chemical synthesis , Benzofurans/chemistry , Breast Neoplasms/drug therapy , Caspase 3/metabolism , Caspase 9/metabolism , Catalytic Domain , Chromones/chemical synthesis , Chromones/chemistry , Doxorubicin/pharmacology , G2 Phase Cell Cycle Checkpoints/drug effects , Humans , Imidazoles/pharmacology , MCF-7 Cells , Mitogen-Activated Protein Kinase 14/chemistry , Molecular Docking Simulation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/chemistry , Pyridines/pharmacologyABSTRACT
Based on the reported high expression of p38α MAP kinase in invasive breast cancers and the activity of different functionalized chromone derivatives as p38α 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 p38α MAP kinase suppressors as new anti-breast cancer tools. Using GOLD program, molecular docking study of the target compounds into p38α 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 0.17µM vs IC50; 0.62µM of doxorubicin. Eleven selected compounds were evaluated for their inhibitory potency against p38α MAPK kinase. The derivatives IVa, Va,b, VIa, IXb and XIIIa represented significant activity (IC50; 0.19-0.67µM) comparing to the reference drug SB203580 (IC50; 0.50µM). In virtue of its promising cytotoxic and p38α 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.
