title: Synthesis and molecular docking studies of new furochromone derivatives as p38α MAPK inhibitors targeting human breast cancer MCF-7 cells.
abstract: 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 IC50values 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.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Egypt.
authors.forename: Kamelia M
authors.initials: KM
authors.lastname: Amin
authors.affiliation: Department of Therapeutical Chemistry, National Research Centre, Dokki, Cairo 12622, Egypt. Electronic address: yasmin_syam@yahoo.com.
authors.forename: Yasmin M
authors.initials: YM
authors.lastname: Syam
authors.affiliation: Department of Therapeutical Chemistry, National Research Centre, Dokki, Cairo 12622, Egypt.
authors.forename: Manal M
authors.initials: MM
authors.lastname: Anwar
authors.affiliation: Pharmaceutical Sciences Dept., Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, TX, USA.
authors.forename: Hamed I
authors.initials: HI
authors.lastname: Ali
authors.affiliation: Department of Pharmacology, Faculty of Pharmacy, Al-Azhar University, Egypt.
authors.forename: Tamer M
authors.initials: TM
authors.lastname: Abdel-Ghani
authors.affiliation: Inaya Medical College, Riyadh, Saudi Arabia.
authors.forename: Aya M
authors.initials: AM
authors.lastname: Serry
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000473:pathology*; D066241:Carbon-13 Magnetic Resonance Spectroscopy; D020134:Catalytic Domain; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D005260:Female; D006801:Humans; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D047428:Protein Kinase Inhibitors; D066244:Proton Magnetic Resonance Spectroscopy; D021241:Spectrometry, Mass, Electrospray Ionization; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
chemical_list: D002867:Chromones; D047428:Protein Kinase Inhibitors; D048051:p38 Mitogen-Activated Protein Kinases
keywords: Cell cycle arrest; Furochromones; MCF-7 cell lines; Molecular docking; p38α MAP kinase