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Design and synthesis of sugar nucleotide analogues as the inhibitors against glycosyltransferases

Research Project

Project/Area Number 17590024
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Chemical pharmacy
Research InstitutionKyoto Pharmaceutical University

Principal Investigator

KAJIMOTO TETSUYA  Kyoto Pharmaceutical University, Department of Pharmaceutical Sciences, Associate Prof., 薬学部, 助教授 (80185777)

Co-Investigator(Kenkyū-buntansha) TSUJI SHUICHI  Tokai University, Institute of Future Science and Technology, Professor, 未来科学技術共同センター, 教授 (90124677)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2006: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
Keywordsglycosyltransferase / inhibitor / sugar nucleotide analogues / nikkomycin / polyoxin / acceptor treisaccharide / enzymatic aldol reaction / L-threonine aldolase / thymine polyoxin C / 糖ヌクレオチド / β-ヒドロキシ-α-L-アミノ酸 / UDP-GlcNAc / GDP-Fuc / Candida humicola
Research Abstract

Inhibitors against glycosyltransferases and glycosidases, which build up oligosaccharide moieties of biologically active glycoconjugates, are essential tools for the development of glycobiology and promising candidates of novel agents for the treatments of tumors, inflammatory, autoimmune diseases, and bacterial and virus infections. Many excellent inhibitors against glycosidases, such as deoxynojirimycin and oseltamivir, were found from nature and developed by good combination of structural biology and synthetic chemistry. However, excellent inhibitors of glycosyltransferases have not been developed until recently, because of little information on the structures of active sites of the enzymes, involvement of several components in the transition state of the enzyme catalyzed reaction, low affinities between the enzymes and substrates, and no facile assay systems for the inhibitory activities. Therefore, we embarked on design and synthesis of sugar nucleotide analogues as the inhibitors against glycosyltransferases since the sugar nulcleotides are donor substrates of the enzymes. Fortunately, nikkomycin and polyoxins, peptidic analogues of sugar nucleotide are already used practically for the treatment of some skin diseases caused by Candida sp. and as agrochemicals. Thus, we started these compounds by using L-threonine aldolase-catalyzed enzymatic aldol reaction, which afford fl-hydroxy-cc-L-amino acids under completely physiological conditions. Finally, we succeeded in the formal total synthesis of polyoxin C in good overall yield in the shortest step within those reported so far. In addition, a trisaccharide which could be an acceptor substrate of N-acetylglucosaminyltransferase V was faciley synthesized by using thioglycosyl donor, which was prepared by using novel odorless benzenethiols.

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (18 results)

All 2007 2006 2005

All Journal Article (18 results)

  • [Journal Article] Development of Odorless Organosulfur Reagents and Asymmetric Reaction Using Odorless Thiols2007

    • Author(s)
      T.Kajimoto, M.Node
    • Journal Title

      Heteroatom Chem. (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Synthesis of thymine polyoxin C by using L-threonine aldolase-catalyzed reaction2007

    • Author(s)
      T.Nishiyama, S.S.Mohile, T.Kajimoto, M.Node
    • Journal Title

      Heterocycles Vol. 71(in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Synthesis of thymine polyoxine C by using L-threonine aldolase-catalyzed aldol reaction2007

    • Author(s)
      T.Nishiyama, S.S.Mohire, T.Kajimoto, M.Node
    • Journal Title

      Heterocycles 71(in press)

    • NAID

      40015400294

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Synthesis of thymine polyoxine C by using L-threonine aldolase-catalyzed aldol Reaction2007

    • Author(s)
      T.Nishiyama, S.S.Mohire, T.Kajimoto, M.Node
    • Journal Title

      Heterocycles 71(In press)

    • NAID

      40015400294

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Odorless Benzenethiols in the Synthesis of Thio-Glycosides and Its Application for Glycosylation Reactions2006

    • Author(s)
      T.Kajimoto, Y.Ishioka, T.Katoh, M.Node
    • Journal Title

      Bioorg. Med. Chem. Lett. Vol. 16

      Pages: 5736-5739

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Synthesis of Inhibitors against Glycosyltransferases2006

    • Author(s)
      T.Kaj imoto, M.Node
    • Journal Title

      J. Syn. Org. Chem. Jpn. Vol. 64

      Pages: 894-912

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Odorles Benzenethiols in the Synthesis of Thioglycosides and Its Application for Glycosylation Reactions2006

    • Author(s)
      T.Kajimoto, Y.Ishioka, T.Katoh, M.Node
    • Journal Title

      Bioorg. Med. Chem. Lett. 16

      Pages: 5736-5739

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Synthesis of Inhibitors against Glycosyltransferases2006

    • Author(s)
      T.Kajimoto, M.Node
    • Journal Title

      J. Syn. Org. Chem. Jpn. 64

      Pages: 894-912

    • NAID

      10018052161

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Odorles Benzenethiols in the Synthesis of Thioglycosides and Its Application for Glycosylation Reactions2006

    • Author(s)
      T.Kajimoto, Y.Ishioka, T.Katoh, M.Node
    • Journal Title

      Bioorg.Med.Chem.Lett. 16

      Pages: 5736-5739

    • Related Report
      2006 Annual Research Report
  • [Journal Article] 糖転移酵素に対する阻害剤の合成2006

    • Author(s)
      梶本哲也, 野出学
    • Journal Title

      有機合成化学協会誌 64

      Pages: 894-912

    • NAID

      10018052161

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Fluorescence modification of Gb3 oligosaccharide and rapid synthesis of oligosaccharide moieties using fluorous protective group.2005

    • Author(s)
      T.Miura, S.Tsujino, A.Satoh, K.Goto, M.Mizuno, M.Nouchi, T Kajimoto, et al.
    • Journal Title

      Tetrahedron Vol. 61

      Pages: 6518-6526

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] The application of phenylmethanethiol and benzene-thiol derivatives as odorless organosulfur reagents in the synthesis of thiosugars and thioglycosides.2005

    • Author(s)
      J.Hasegawa, M.Hamada, T.Miyamoto, K.Nishide, T.Kajimoto, J.Uenishi, M.Node
    • Journal Title

      Carbohydr. Res. Vol. 340

      Pages: 2360-2368

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Fluorescence modification of Gb3 oligosaccharide and rapid synthesis of oligosaccharide moieties using fluorous protective group2005

    • Author(s)
      T.Miura, S.Tsujino, A.Satoh, K.Goto, M.Mizuno, M.Noguchi, T.Kajimoto, M.Node, Y.Murakami, N.Imai, T.Inazu
    • Journal Title

      Tetrahedron 61

      Pages: 6518-6526

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] The application of phenylmethanethiol and benzenethiol derivatives as odorless organo- sulfur reagents in the synthesis of thiosugars and thioglycosides2005

    • Author(s)
      J.Hasegawa, M.Hamada, T.Miyamoto, K.Nishide, T.Kajimoto, J.Uenishi, M.Node
    • Journal Title

      Carbohydr. Res. 340

      Pages: 2360-2368

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Effects of disialoganglioside GD3 on mitochondrial membrane potential2005

    • Author(s)
      Y.Higuchi, T.Miura, T.Kajimoto, Y.Ohta
    • Journal Title

      FEBS Letters 579

      Pages: 3009-3013

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Design and Facile Synthesis of Neoglycolipids as Lactosylceramide Mimetics and Their Tansformation into glycoliposomes.2005

    • Author(s)
      Y.Harada, T.Murata, K.Totani, T.Kajimoto, et al.
    • Journal Title

      Biosci.Biotechnol.Biochem. 69(1)

      Pages: 166-178

    • Related Report
      2005 Annual Research Report
  • [Journal Article] The application of phenylmethanethiol and benzenethiol derivatives as odorless organosulfur reagents in the synthesis of thiosugar and thioglycosides2005

    • Author(s)
      J.Hasegawa, M.Hamada, T.Miyamoto, K.Nishide, T.Kajimoto, et al.
    • Journal Title

      Carbohydr.Res. 340

      Pages: 2360-2368

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Fluorecence modification of Gb3 oligosaccharide and rapid synthesis of oligosaccharide moieties using fluorous protecting group2005

    • Author(s)
      T.Miura, S.Tsujino, A.Satoh, K.Goto, M.Mizuno, M.Noguchi, T.Kajimoto, et al.
    • Journal Title

      Tetrahedron 61

      Pages: 6518-6526

    • Related Report
      2005 Annual Research Report

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Published: 2005-04-01   Modified: 2016-04-21  

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