title: Molecular modeling studies and synthesis of novel methyl 2-(2-(4-oxo-3-aryl-3,4-dihydroquinazolin-2-ylthio)acetamido)alkanoates with potential anti-cancer activity as inhibitors for methionine synthase.
abstract: Cobalamin-dependant cytosolic enzyme methionine synthase (MetS) catalyses the transfer of a methyl group from the methyltetrahydrofolate (MTHF) to homocysteine (Hcy) to produce methionine and tetrahydrofolate (THF). MetS is over-expressed in the cytosol of certain breast and prostate tumour cells. Methionine used as a source of one carbon atom for the building of the DNA of the tumour cells, structural protein and enzymes. In this study, we designed, synthesized and evaluated the cytotoxic activity of a series of substituted methyl 2-(2-(4-oxo-3-aryl-3,4-dihydroquinazolin-2-ylthio)acetamido)acetate and dipeptide that mimic the substructure of MTHF. These inhibitors were docked in to the MTHF binding domain in such the same way as MTHF in its binding domain. The free energies of the binding were calculated and compared to the IC50 values. This series has been developed by dicyclohexylcarbodiimide (DCC) and azide coupling methods of amino acid esters with carboxylic acid derivatives, respectively. Compound methyl 3-hydroxy-2-(2-(3-(4-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-2-ylthio)acetamido)propanoate exhibited the highest IC50 value 20 µg/mL against PC-3 cell line and scored the lowest free energy of the binding (-207.19 kJ/mol).
authors.affiliation: Department of Chemistry, Faculty of Science, Suez Canal University.
authors.forename: Ismail Mahmoud
authors.initials: IM
authors.lastname: Elfekki
authors.forename: Walid Fathalla Mohamed
authors.initials: WF
authors.lastname: Hassan
authors.forename: Hosam Eldin Abd Elhamed
authors.initials: HE
authors.lastname: Elshihawy
authors.forename: Ibrahim Ahmed Ibrahim
authors.initials: IA
authors.lastname: Ali
authors.forename: Elsayed Hussein Mostafa
authors.initials: EH
authors.lastname: Eltamany
mesh_terms: D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001665:Binding Sites; D045744:Cell Line, Tumor; D030562:Databases, Protein; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D005492:Folic Acid / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D062105:Molecular Docking Simulation; D017434:Protein Structure, Tertiary; D011799:Quinazolines / Q000737:chemistry*; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011799:Quinazolines; C032418:5,11-methenyltetrahydrohomofolate; D005492:Folic Acid; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase