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Synthesis of adenine derivatives possessing interferon inducing activity and creation of receptor ligand with high affinity

Research Project

Project/Area Number 16590087
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

HIROTA Kosaku  Gifu Pharmaceutical University, professor, 薬学部, 教授 (90082982)

Co-Investigator(Kenkyū-buntansha) SAJIKI Hironao  Gifu Pharmaceutical University, Associate Professor, 薬学部, 助教授 (50275096)
MAEGAWA Tomohiro  Gifu Pharmaceutical University, Assistant, 薬学部, 助手 (40363890)
Project Period (FY) 2004 – 2005
Project Status Completed (Fiscal Year 2005)
Budget Amount *help
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2004: ¥2,400,000 (Direct Cost: ¥2,400,000)
Keywordsinterferon-inducing activity / 8-hydroxyadenine / deazaadenine / tool-like receptor / TRL-7 / affinity ligand / fluorescence ligand / インターフェロン誘導活性 / 1-デアザアデニン / 3-デアザアデニン / アデニン / インターフェロン誘導剤
Research Abstract

Recently, we found that 9-benzyl-8-hydroxyadenine (1)possesses relatively potent interferon (IFN)-inducing activity as a lead compound. Further effort to establish the structure-activity relationship reached 2-butoxy- 9-bennzyl- 8-hydroxyandenine (2)as the most active compounds, whose potencies were 10^4-fold greater than that of the lead compound (1). In this research synthesis of higher active analog and fluorescent ligand for Toll-like receptor 7 (TLR-7), whose agonist is such 8-hydroxyandenies, were investigated and the following results were obtained.
1)Chemical modification of the 2-position of adenines : Introduction of various substituents into the 2-position were attempted. 2-MeO(CH_2)_2O- and 2-MeOCH_2S- analogs indicated similar activity to compound 2.
2)Synthesis of 1- or 3- deazaadenine derivatives : The oral bioavailability of compound 2 is remarkably low. Synthesis of 1- or 3-deaza analogs, which are expected increase of lipophilicity, was planed to improve the oral absorption of compound 2. Synthesis of 9-benzyl-2-butoxy-3-deazaadenine (3) and 9-Benzyl-2-butoxy-1-deazaadenine (4) were establiched using 4-amino-2,6-dichloropyridine as a starting compound. Now introduction of an 8-hydroxy group into the deazaadenines (3 and 4) is carried out.
3)Synthesis of fluorescent ligand for Toll-like receptor 7 (TLR-7) : 8-Hydroxyadenine (2) is a strong agonist of TLR-7 and mutual interaction causes production of a large amount of IFN. Synthesis of 8-hydroxyadenine derivative possessing a fluorescent functional group instead of benzyl group at the 9-position was investigated as a probe for analysis of the structure and function of TLR-7. Introduction of anthranylmethyl group resulted in failure in performance caused by low solubility. Various synthetic approaches are now under investigation.

Report

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

    (5 results)

All 2005 2004

All Journal Article (5 results)

  • [Journal Article] Synthesis and evaluation of 2-substituted 8-hydroxyadenines as potent interferon inducers with improved oral bioavailabilities2005

    • Author(s)
      A.Kurimoto, T.Ogino, S.Ichii, H.Y.Isobe, M.Tobe, H.Ogita, H.Takaku, H.Sajiki, K.Hirota, H.Kawakami
    • Journal Title

      Bioorganic & Medicinal Chemistry 12

      Pages: 1091-1099

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Synthesis and evaluation of 2-substituted 8-hydroxyadenines as potent interferon inducers with improved oral bioavailabilities2004

    • Author(s)
      A.Kurimoto, T.Ogino, S.Ichii, H.Y.Isobe, M.Tobe, H.Ogita, H.Takaku, H.Sajiki, K.Hirota, H.Kawakami
    • Journal Title

      Bioorganic & Medicinal Chemistry 12・5

      Pages: 1091-1099

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] インターフェロン誘導活性を有するアデニン誘導他の合成と構造活性相関に関する研究2004

    • Author(s)
      風岡和憲, 佐治木弘尚, 廣田耕作
    • Journal Title

      岐阜薬科大学紀要 53

      Pages: 1-12

    • 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
  • [Journal Article] Synthesis and structure-activity relationship of adenine derivatives with interferon-inducing activity2004

    • Author(s)
      K.Kazaoka, H.Sajiki, K.Hirota
    • Journal Title

      Gifu Yakka Daigaku Kayo 53

      Pages: 1-12

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2005 Final Research Report Summary
  • [Journal Article] Synthesis and evaluation of 2-substituted 8-hydroxyadenines as potent interferon inducers with improved oral bioavailabilities2004

    • Author(s)
      A.Kurimoto, T.Ogino, S.Ichii, H.Sajiki, K.Hirota, H.Kawakami
    • Journal Title

      Bioorganic & Medicinal Chemistry 12・5

      Pages: 1091-1099

    • Related Report
      2004 Annual Research Report

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

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