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Development of new antifungal and anti-HIV agents based on the mannose binding quinone glycoside

Research Project

Project/Area Number 16580090
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Bioproduction chemistry/Bioorganic chemistry
Research InstitutionToyama Prefectural University

Principal Investigator

IGARASHI Yasuhiro  Toyama Prefectural University, Department of Engineering, Associate Professor, 工学部, 助教授 (20285159)

Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥2,400,000 (Direct Cost: ¥2,400,000)
Fiscal Year 2005: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2004: ¥1,600,000 (Direct Cost: ¥1,600,000)
Keywordspradimicin / antifungal / anti-HIV / Pradimicin
Research Abstract

In order to improve the pharmacokinetics of antifungal antibiotic pradimicins, synthesis of new derivatives that have higher water solubility and lower self aggregation property was investigated in this study. After examining several derivatives, it was found that the new derivatives designated PRM-DCA have desired properties. PRM-DCA was obtained by the oxidative cleavage of 1,2-diols in the xylose moiety and the following oxidation of aldehyde to carboxylic acid. Thus, the new derivatives possess two carboxylic acid functionalities in their sugar part. Pradimicin A, N,N-dimethylpradimicin C, and BMY-28864 were subjected to the oxidative conversion and the PRM-DCA derivatives were obtained in 60-75% isolation yield. The solubility of the PRM-DCA in PBS solution was enhanced in comparison with the parent compounds : ca. 30 times in case of pradimicin A, and ca. 2 times in case of N,N-dimethylpradimicin C and BMY-28864. The affinity of PRM-DCA derivatives to D-mannose was decreased 20 times compared to the parent compounds. The aggregation of PRM-DCA derivatives with mannan was less than 5% of the parent compounds in case of pradimicin A and N,N-dimethylpradimicin C, and less than 30% in case of BMY-28864. As described above, it was shown that the new derivatives PRM-DCA were prepared in one-pot reaction from the natural products and had high water solubility and low aggregation property. The PRM-DCA derivatives showed antifungal activity against Candida albicans, Cryprococcus neoformans, and Asperigillus fumigatus although the potency was same or weaker than the parent compounds. On the other hand, the new derivatives did not exhibit acvitity against HIV and influenza virus although the parent compounds exhibit good activity against such virus. In addition, PRM-DCA derivatives were shown to be useful as a starting material to synthesize the prodrugs and the drug-conjugates by using the carboxyli acid residues.

Report

(3 results)
  • 2005 Annual Research Report   Final Research Report Summary
  • 2004 Annual Research Report
  • Research Products

    (5 results)

All 2004

All Journal Article (2 results) Book (1 results) Patent(Industrial Property Rights) (2 results)

  • [Journal Article] Mannose-binding quinone glycoside, MBQ : potential utility and action mechanism2004

    • Author(s)
      Yasuhiro Igarashi, Toshikazu Oki
    • Journal Title

      Advances in Applied Microbiology Volume 54

      Pages: 147-166

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Derivatives and use of benzonaphthacene glycoside2004

    • Author(s)
      Toshikazu Oki, Yasuhiro Igarashi, Tamotsu Furumai
    • Journal Title

      Japan Patent (2004.9.6) 200409015

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Book] Advances in Applied Microbiology, volume 542004

    • Author(s)
      Yasuhiro Igarashi, Toshikazu Oki
    • Publisher
      Elsevier Academic Press
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary 2004 Annual Research Report
  • [Patent(Industrial Property Rights)] ベンゾナフタセングリコシド誘導体およびその使用2004

    • Inventor(s)
      沖俊一, 五十嵐康弘, 古米保
    • Industrial Property Rights Holder
      沖俊一, 五十嵐康弘, 古米保
    • Filing Date
      2004-09-06
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Patent(Industrial Property Rights)] ベンゾナフタセングリコシド誘導体およびその使用2004

    • Inventor(s)
      沖 俊一, 五十嵐 康弘, 古米 保
    • Industrial Property Rights Holder
      沖 俊一, 五十嵐 康弘, 古米 保
    • Filing Date
      2004-09-06
    • Related Report
      2004 Annual Research Report

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Published: 2004-04-01   Modified: 2016-04-21  

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