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

• Elfekki Ismail Mahmoud

  Department of Chemistry, Faculty of Science, Suez Canal University

• Hassan Walid Fathalla Mohamed

  Department of Physics and Math. Engineering, Faculty of Engineering, Port-Said University

• Elshihawy Hosam Eldin Abd Elhamed

  Department of Organic Chemistry, Faculty of Pharmacy, Suez Canal University

• Ali Ibrahim Ahmed Ibrahim

  Department of Chemistry, Faculty of Science, Suez Canal University

• Eltamany Elsayed Hussein Mostafa

  Department of Chemistry, Faculty of Science, Suez Canal University

抄録

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).

収録刊行物

• ＣＨＥＭＩＣＡＬ　＆　ＰＨＡＲＭＡＣＥＵＴＩＣＡＬ　ＢＵＬＬＥＴＩＮ

  ＣＨＥＭＩＣＡＬ　＆　ＰＨＡＲＭＡＣＥＵＴＩＣＡＬ　ＢＵＬＬＥＴＩＮ 62 (7), 675-694, 2014

  公益社団法人 日本薬学会

キーワード

• cobalamin: methionine
• methionine synthase
• quinozaline
• thioamide
• chemoselective reaction

詳細情報

• CRID: 1390001204176704128
• NII論文ID: 130004053811
• NII書誌ID: AA00602100
• DOI: 10.1248/cpb.c14-00158
• COI: 1:STN:280:DC%2BC2cfovFSktg%3D%3D
• ISSN: 13475223
• ISSN: 00092363
• NDL書誌ID: 025543217
• PubMed: 24990505
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I025543217
• Web Site: https://www.jstage.jst.go.jp/article/cpb/62/7/62_c14-00158/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2015033849
• 本文言語コード: en
• データソース種別:
  • JaLC
  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
• 抄録ライセンスフラグ: 使用不可