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Synthesis and Biological Evaluation of Difluoromethylenephosphonic Acid Derivatives

Research Project

Project/Area Number 10672001
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Chemical pharmacy
Research InstitutionSchool of Pharmacy,Tokyo University of Pharmacy & Life Science

Principal Investigator

YOKOMATSU Tsutomu  Tokyo University of Pharmacy & Life Science, School of Pharmacy, Associate Professor, 薬学部, 助教授 (70158369)

Project Period (FY) 1998 – 1999
Project Status Completed (Fiscal Year 1999)
Budget Amount *help
¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 1999: ¥600,000 (Direct Cost: ¥600,000)
Fiscal Year 1998: ¥2,200,000 (Direct Cost: ¥2,200,000)
KeywordsPurine nucleoside phosphorylase / Protein-tyrosine phosphatase / Inhibitors / Difluoromethylenephosphonic acids / Structure-activity relation ship / プリンヌクレオシドホスホリラーゼ / プロテインチロシンホスファターゼ / ジフルオロホスホン酸
Research Abstract

1.Synthesis and biological evaluation of novel nucleotide analogues possessing difluoromethylene phosphonic acids. Novel nucleotide analogues derived from connecting purine nucleobases and difluoromethylenephosphonic acid (CFィイD22ィエD2POィイD23ィエD2HィイD22ィエD2) with a variety of alkyl spacer were prepared for "multi-substrate analogue" inhibitors of purine nucleoside phosphorylase (PNPs). The cyclopropane and the tetrahydrofuran moieties of the alkyl spacer connecting a nucleobase and CFィイD22ィエD2POィイD23ィエD2HィイD22ィエD2 were found to be effective for good inhibition of PNPs.
2.Synthesis of α, α-difluorobenzylphosphonic acid derivatives for inhibitors of purotein-tyrosine phosphatase 1B. A series of α, α-difluorobenzylphosphonic acids having a hydrophobic functional group were prepared via the Stille coupling reaction from halogenated α, α-difluorobenzylphosphonates. Evaluation of inhibitory activity toward protein tyrosine phosphatase (PTP 1B) revealed that the ethynyl, phenylthynyl and (E)-styryl groups on the benzene nuclei increased the inhibitory activity upon α, α-defluorobenzylphosphonic acid. Inhibitory activities significantly increased upon introducing both (E)-styryl and bis-methylsulfonamide functional groups onto the benzene nuclei of α, α-difluorobenzylphosphonic acid.

Report

(3 results)
  • 1999 Annual Research Report   Final Research Report Summary
  • 1998 Annual Research Report
  • Research Products

    (17 results)

All Other

All Publications (17 results)

  • [Publications] T. Yokomatsu,: "Enzymatic Desymmetrization of Prochiral 2-Benzyl-1,3-propanediol Derivatives : A Practical Chemoenzymatic Synthesis of Novel Phosphorylated Tyrosine Analogues,"Tetrahedron. 54. 9341-9352 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T. Yokomatsu,: "Synthesis of 1,1-Difluoro-5-(1H-9-purinyl)-2pentenylphonic Acids and the Related Methano Analogues. Remarkable Effect of the Nucleobases and the Cyclopropane Rings・・・・"Bioorg. Med. Chem.. 6. 2495-2505 (1998)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T. Yokomatsu,: "Synthesis and Biological Evaluation of γ, γ-Difluorobenzylphosphonic Acid Derivatives as Small Molecular Inhibitors of Protein-tyrosine Phosphatase 1B"Bioorg. Med. Chem. Lett.. 9. 529-532 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T. Yokomatsu,: "Convenient Synthesis of Cyclopropylalkanol Derivatives Possessing a Difluoromethylenephosphonate Group at the Ring"J. Org. Chem.. 64. 8413-8418 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T. Yokomatsu,: "Synthesis and Biological Evaluation of 1,1-Difluoro-2-(teterahydro-3-furanyl)ethylphosphonic Acids possessing aN9-purinylmethy Functional Group at the Ring. A New Class of Inhibitor for・・・・"Bioorg. Med. Chem. Lett.. 9. 2833-2836 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T. Yokomatsu,: "Synthesis of novel nucleotide analogues possessing a difuluoromethylenephosphonato group. Evaluation of the inhibitory activity for purine nucleoside phosphorylase"Nucleic Acids Symposium Series. 38. 27-28 (1999)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T.Yokomatsu, T.Minowa, T.Murano, and S.Shibuya: "Enzymatic Desymmetrization of Prochiral 2-Benzyl-1, 3-propanediol Derivatives : A Practical Chemoenzymatic Synthesis of Novel Phosphorylated Tyrosine Analogues"Tetrahedron. 54. 9341-9352 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T.Yokomatsu, H.Abe, M.Sato, K.Suemune, T.Kihara, S.Soeda, H.Shimeno, and S.Shibuya: "Synthesis of 1, 1-Difluoro-5-(1H-9-purinyl)-2-pentenylphosphonic Acids and the Related Methano Analogues. Remarkable Effect of the Nucleobases and the Cyclopropane Rings on Inhibitory Activity toward Purine Nucleoside Phosphorylase"Bioorg.Med.Chem.. 6. 2495-2505 (1998)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T.Yokomatsu, T.Murano, I.Umesue, S.Soeda, H.Shimeno, and S.Shibuya: "Synthesis and Biological Evaluation of α,α-Difluorobenzylphosphonic Acid Derivatives as Small Molecular Inhibitors of Protein-tyrosine Phosphatase 1B."Bioorg.Med.Chem.Lett.. 9. 529-532 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T.Yokomatsu, H.Abe, T.Yamagishi, K.Suemune, and S.Shibuya: "Convenient Synthesis of Cyclopropylalkanol Derivatives Possessing a Difluoromethylenephosphonate Group at the Ring."J.Org.Chem.. 64. 8413-8418 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T.Yokomatsu, Y.Hayakawa, K.Suemune, T.Kihara, S.Soeda, H.Shimeno, and S.Shibuya: "Synthesis and Biological Evaluation of 1, 1-Difluoro-2-(teterahydro-3-furanyl)ethylphosphonic Acids possessing a N9-Purinylmethyl Functional Group at the Ring. A New Class of Inhibitor for Purine Nucleoside Phosphorylases"Bioorg.Med.Chem.Lett.. 9. 2833-2836 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T.Yokomatsu, Y.Hayakawa, H.Abe, S.Shibuya, T.Kihara, S.Soeda, and H.Shimeno: "Synthesis of novel nucleotide analogues possessing a difluoromethylenephosphonato group. Evaluation of the inhibitory activity for purine nucleoside phosphorylase"Nucleic Acids Symposium Series. 38. 27-28 (1999)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1999 Final Research Report Summary
  • [Publications] T.Yokomatsu: "Synthesis and Biological Evaluation of 1,1-Difluoro-2-(teterahydro-3-furanyl)ethylphosphonic Acids possessing a N9-Purinylmethyl Functional Group at the Ring.A New Class of Inhibitor---"Bioorg.Medd.Chem.Lett.. 9. 2833-2836 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] T.Yokomatsu: "Convenient Synthesis of Cyclopropylalkanol Derivatives Possessing a Difluoromethylenephosphonate Group at the Ring"J.Org.Chem.. 64. 8413-8418 (1999)

    • Related Report
      1999 Annual Research Report
  • [Publications] Tsutomu Yokomatsu: "Enzymatic Desymmetrization of Prochiral 2-Benzyl-1,3-propanediol Derivatives:A Practical Chemoenzymatic Synthesis of Novel Phosphorylated Tyrosine Analogues" Tetrahedron. 54. 9341-9356 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tutomu,Yokomatsu: "Synthesis of 1,1-Difluoro-5-(1H-9-purinyl)-2-pentenylphosphonic Acids and the Related Methano Analogues. Remarkable Effect of the Nucleobases and the Cyclopropane Rings on Inhibitory Activity toward Purine Nucleoside Phosphorylase." Bioorg.Med.Chem.6(12). 2495-2505 (1998)

    • Related Report
      1998 Annual Research Report
  • [Publications] Tutomu,Yokomatsu: "Synthesis and Biological Evaluation of α,α-Difluorobenzylphosphonic Acid Derivatives as Small Molecular Inhibitors of Protein-tyrosine Phosphatase 1B." Bioorg.Med.Chem.Lett.9(4). 529-532 (1999)

    • Related Report
      1998 Annual Research Report

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Published: 1998-04-01   Modified: 2016-04-21  

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