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Construction of focused library and the development of protein tyrosine phosphatase inhibitor

Research Project

Project/Area Number 15310144
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Living organism molecular science
Research InstitutionTOHOKU UNIVERSITY

Principal Investigator

SODEOKA Mikiko  TOHOKU UNIVERSITY, INSTITUTE OF MULTIDISCIPLINARY RESEARCH FOR ADVANCED MATERIALS, ASSOCIATE PROFESSOR, 多元物質科学研究所, 教授 (60192142)

Co-Investigator(Kenkyū-buntansha) HIRAI Go  RIKEN, Research Scientist, 理化学研究所, 研究員 (50359551)
HAMASHIMA Yoshitaka  TOHOKU UNIVERSITY, INSTITUTE OF MULTIDISCIPLINARY RESEARCH FOR ADVANCED MATERIALS, Research Associate, 多元物質科学研究所, 助手 (40333900)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥15,700,000 (Direct Cost: ¥15,700,000)
Fiscal Year 2004: ¥7,300,000 (Direct Cost: ¥7,300,000)
Fiscal Year 2003: ¥8,400,000 (Direct Cost: ¥8,400,000)
Keywordsfocused library / protein tyrosine phosphatase / inhibitor / tetronic acid / RK-682 / Ascorbic acid / heparanase / protein kinase C / ライブラリー / テロン酸
Research Abstract

Aiming at developing PTP (protein tyrosine phosphatase), a "focused-library" (compounds having a "core" structure that can interact with the conserved catalytic site of PTP as a phosphate mimic and having "various" substituents that may interact with the unique region of each enzyme) was synthesized. Construction of a new library having L-ascorbic acid as a "core" structure was examined. We have already developed an efficient method for carbamate synthesis using a polymer-supported N-hydroxysuccinimide (NHS). Using this method an ascorbic acid-carbamate library was synthesized. The carbamate derivatives were prepared either from 6-amino-ascorbic acid and various alcohols, or from 5-dehydroxy-ascorbic acid and various amines. The inhibitory activity of these compounds (about 80 compounds) toward PTP1B (PTP) was tested, and several compounds showed the moderate inhibitory activity.
The 4-O-alkyated tetronic acid derivatives as second generation library was synthesized, and 4-benzyl-RK-682 has been found to possess a selective inhibitory activity for heparanase. 4-Benzyl-RK-682 also inhibited the invasion and migration of human fibrosarcoma HT 1060 cells.
The isobenzofuranone library was also synthesized, and among them we have found the strong PKCα activators.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (14 results)

All 2005 2004 2003 Other

All Journal Article (12 results) Publications (2 results)

  • [Journal Article] 低分子阻害剤によるタンパク質リン酸化の制御 : 構造変化と選択性2005

    • Author(s)
      平井 剛
    • Journal Title

      実験医学増刊 23, No.4

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] An Efficient Catalytic Enantioselective Fluorination of β-Ketophosphonates Using Chiral Palladium Complexes.2005

    • Author(s)
      Yoshitaka Hamashima
    • Journal Title

      Tetrahedron Lett. 46

      Pages: 1447-1450

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Control of the protein phosphorylation by small molecule inhibitors : protein structure and selectivity2005

    • Author(s)
      Go Hirai
    • Journal Title

      Experimental Medicine vol.23-No.4

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] An Efficient Catalytic Enantioselective Fluorination of β-Keto-phosphonates Using Chiral Palladium Complexes.2005

    • Author(s)
      Yoshitaka Hamashima
    • Journal Title

      Tetrahedron Lett. Vol.46

      Pages: 1447-1450

    • Related Report
      2004 Annual Research Report
  • [Journal Article] 低分子阻害剤によるタンパク質リン酸化の制御:構造変化と選択性2005

    • Author(s)
      平井 剛
    • Journal Title

      実験医学増刊 Vol.23,No.4

      Pages: 199-204

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Design, Synthesis, and Structure-Activity Relationship of New Isobenzofuranone Ligands of Protein Kinase C.2004

    • Author(s)
      Yoshiyasu Baba
    • Journal Title

      Bioorg.Med.Chem.Lett. 114

      Pages: 2963-2967

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Evaluation of Series of Isobenzofuranone Dimers as PKCα Ligands : Implication for the Distance between the Two Ligand Binding Sites.2004

    • Author(s)
      Yoshiyasu Baba
    • Journal Title

      Bioorg.Med.Chem.Lett. 114

      Pages: 2969-2972

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Structure-based Design of a Selective Heparanase Inhibitor as an Antimetastatic Agent.2004

    • Author(s)
      Keisuke Ishida
    • Journal Title

      Mol.Cancer Therapeutics 3

      Pages: 1069-1077

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Design, Synthesis, and Structure-Activity Relationship of New Isobenzofuranone Ligands of Protein Kinase C.2004

    • Author(s)
      Yoshiyasu Baba
    • Journal Title

      Bioorg.Med.Chem.Lett. Vol.14

      Pages: 2963-2967

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Evaluation of Series of Isobenzofuranone Dimers as PKCα Ligands : Implication for the Distance between the Two Ligand Binding Site2004

    • Author(s)
      Yoshiyasu Baba
    • Journal Title

      Bioorg.Med.Chem.Lett. Vol.14

      Pages: 2969-2972

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Structure-based Design of a Selective Heparanase Inhibitor as an Antimetastatic Agent.2004

    • Author(s)
      Keisuke Ishida
    • Journal Title

      Mol.Cancer Therapeutics Vol.3

      Pages: 1069-1077

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Structure-Based Design of a Highly Selective Catalytic Site-Directed Inhibitor of Ser/Thr Protein Phosphatase 2B (Calcineurin)2003

    • Author(s)
      Yoshiyasu Baba
    • Journal Title

      J.Am.Chem.Soc. 125

      Pages: 9740-9749

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Publications] Y.Baba, Y.Ogoshi, G.Hirai, T.Yanagisawa, K.Nagamatsu, S.Mayumi, Y.Hashimoto, M.Sodeoka: "Design, Synthesis, and Structure-Activity Relationship of New Isobenzofuranone Ligands of Protein Kinase C."Bioorg.Med.Chem.Lett.. Vol.14(In Press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Y.Baba, S.Mayumi, G.Hirai, H.Kawasaki, Y.Ogoshi, T.Yanagisawa, Y.Hashimoto, M.Sodeoka: "Evaluation of Series of Isobenzofuranone Dimers as PKCa Ligands : Implication for the Distance between the Two Ligand Binding Sites"Bioorg.Med.Chem.Lett.. Vol.14(In Press). (2004)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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