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Synthesis and Biological Activities of 4'-Thionucleosides branched at the Sugar Portion

Research Project

Project/Area Number 15590100
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Drug development chemistry
Research InstitutionShowa University

Principal Investigator

HARAGUCHI Kazuhiro  Showa University, Associate Professor, 薬学部, 助教授 (10218638)

Co-Investigator(Kenkyū-buntansha) TANAKA Hiromichi  Showa University, Professor, 薬学部, 教授 (50109477)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥2,900,000 (Direct Cost: ¥2,900,000)
Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2003: ¥1,500,000 (Direct Cost: ¥1,500,000)
Keywordsnucleoside / glycal / thio-glycosidation / thymidine / lithiation / reduction / anti-viral / チオグリコシル化反応 / リチム化反応 / リナウム化反応 / wittig反応 / 血管新生阻害 / 抗ガン剤
Research Abstract

When 3,5-O-(Tetraisopropyldisiloxane-1,3-diyl)-4-thiofuranoid glycal (1) was lithiated with lithium diisopropylamide (LDA) and the resultingl-lithio species (2) was treated with carbon electmphile, 1-carbon-substituted 4-thiofuranoid glycal (3) could be obtained in good yield. Electaophilic glyoosidation between the glycal 3 and silylated thymine was carried out in the presence of phenylselenenyl chloride (PhSeCI) or N-iodosuccinimide (NIS) to funish the β-anomer of 4'-thionudeoside (4), stereoselectively. The glycosylated product 4 was subjected to tin radical-mediated reduction to give the target 1'-carbon-substituted 4'-thiothymidine (5).
The reaction of 1-lithio derivative 2 with benzenesulfonyl chloride gave 1-chloro-glycal 6. When 6 was treated with lithium 2,2,6,6-tetramethylpiperidide (LTMP), C-2 lithiation proceeded to provide 1-chloro-2-lithioglycal 7. Reaction of 7 with carbon electrophile gave the corresponding 2-carbon-substituted 1-chloroglycal 8. The chloro-substituent of 8 could be removed by Birch reduction to furnish 2-carbon-substituted glycal 9. PbSeCl-mediated electrophilic glycosidation between 9 and silylated thymine gave β-anomer of the glycosidated product 10, stereoselectively. When 10 was treated with tributyltin hydride in the presence of triethylborane under 0_2 atmosphere at-30゜C, the target 2'-f3-carbon-substituted 4'-thiothymidine derivative 11.
Finally, 5 and 11 was desilylated with tetrabutylammonium fluoride to furnish 1'- and 2'-β-carbon-substituted 4'-thiothymidine 12 and 13. Among the novel nucleoside analogues synthesized in this study, 1'-methyl-4'-thiothymidine 14 was found to showed anti-HSV-1 activity and anti-angiogenic activity.

Report

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

    (10 results)

All 2004 2003 Other

All Journal Article (9 results) Publications (1 results)

  • [Journal Article] Novel Stereoselective Entry to 2'-β-Carbon-Substituted 2'-Deoxy-4'-thionucleosides from 4-Thiofuranoid Glycals2004

    • Author(s)
      Kazuhiro Haraguchi
    • Journal Title

      Org.Lett. 6

      Pages: 2465-2468

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Synthesis and Antiviral Activities of 1'-Carbon-substituted 4'-Thiothymidines2004

    • Author(s)
      Kazuhiro Haraguchi
    • Journal Title

      Bioorg.Med.Chem. 12

      Pages: 5309-5316

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Novel Stereoselective Entry to 2'-β-Carbon-Substituted 2'-deoxy-4'-thionucleosides from 4-Thiofuranoid Glycal2004

    • Author(s)
      Haraguchi, K. et al.
    • Journal Title

      Org.Lett. 6

      Pages: 2465-2468

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Synthesis and antiviral Activities of 1'-Carbon-Substituted 4'-Thiothymidines2004

    • Author(s)
      Haraguchi, K. et al.
    • Journal Title

      Bioorganic Med.Chem. 12

      Pages: 5309-5316

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Novel Stereoselective Entry to 2'-β-Carbon-Substituted 2'-Deoxy-4'-thionucleoscides from 4-Thiofuranoid Glycals2004

    • Author(s)
      Kazuhiro Haraguchi
    • Journal Title

      Org.Lett. 6

      Pages: 2645-2648

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Synthesis and Antiviral Activities of 1'-Carbon-substituted 4'-Thio-thymidines2004

    • Author(s)
      Kazuhiro Haraguchi
    • Journal Title

      Bioorg.Med.Chem 12

      Pages: 5309-5316

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Stereoselective Synthesis of 2'-β-Carbon-substituted 2'-deoxy-4'-thio-ribonucleosides from 4-Thiofuranoid glycal2003

    • Author(s)
      Kazuhiro Haraguchi
    • Journal Title

      Nucleic Acids Research Supplement 3

      Pages: 7-8

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Stereoselective Synthesis of 2'-β-Carbon-sunstituted 2'-deoxy-4'-thioribonucleosides from 4-Thiofuranoid gycal2003

    • Author(s)
      Haraguchi, K. et al.
    • Journal Title

      Nucleic Acids Research Suppl. 3

      Pages: 7-8

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Stereoselective Synthesis of 2'-β-Carbon-substituted 2'-deoxy-4'-thio-ribonucleosides from 4-Thiofuranoid glical2003

    • Author(s)
      Kazuhiro Haraguchi
    • Journal Title

      Nucleic Acids Research Supplement 3

      Pages: 7-8

    • Related Report
      2004 Annual Research Report
  • [Publications] Kazuhiro Haraguchi: "4-Thioburanoid Glycals : Versatile Synthons for Stereoselective synthesis of 4'-Thionucleosides"Nucleosides, Nucleotides and Nucleic Acids. 22. 763-765 (2003)

    • Related Report
      2003 Annual Research Report

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

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