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Synthesis and Biological Evaluation of Spiroketal Derivatives

Research Project

Project/Area Number 18590027
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Chemical pharmacy
Research InstitutionThe Institute of Physical and Chemical Research

Principal Investigator

TAKESHI Shimizu  The Institute of Physical and Chemical Research, Synthetic Organic Chemistry, Scenior Scientist (80087569)

Co-Investigator(Kenkyū-buntansha) USUI Takeo  University of Tsukuba, Graduate School of Life and Environmental Sciences, Associate Professor (60281648)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥4,020,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥420,000)
Fiscal Year 2007: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
Keywordsreveromvcin A / spirofungin A / spirofuneinB / 6.6-spiroketal / bioprobe / isoleucyl-tRNA svnthetase / osteoclast / structure-activity relationship / 1,2-ジヒドロリベロマイシン / 抗生物質
Research Abstract

Reveromycin A is a 6, 6-spiroketal antibiotic isolated from the genus Streptomyces and shows strong biological activities that makes it potentially useful as an antitumor drug based on inhibition of isoleucyl-tRNA synthetase. Reveromycin A is also expected as a therapeutic agent for hypercalcemia and bone disease. Spirofungins A and B are also polyketide-type antibiotics isolated from Streptomyces violaceusniger Tu 4113 as a mixture in the ratio of 4: 1 and show various antifungal activities, particularly against yeasts. Various derivatives of reveromycin A and spirofungin A, focusing on the 5S hydroxyl group and C18 hemisuccinyl group, were synthesized and their inhibitory effects on both the isoleucyl-tRNA synthetase activity and the survival of osteoclasts, and activities on the morphological reversion of src^<ts>-NRK cells were examined. It was found that 2, 3-dihydroreveromycin A, 4-hydrox3rreveromycin A and the 3, 5-dihydroxyl derivative are the promising derivative of reveromycin A based on the activity and stability. We have developed a novel method for the preparation of the succinates of tertiary alcohols for the synthesis of reveromycin A. 3-Butyn-1-ol was converted into a lactone in eleven steps. Oxidative cleavage of the dihydropyrans prepared via the palladium-catalyzed coupling of the ketene acetal triflates and zinc homoenolate with 0_s0_4-Pb (OAc) _4 gave the succinates of tertiary alcohols. Then, the succinates were converted into the 6, 6-spiketal via the coupling with an alkyne.

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (9 results)

All 2008 2007

All Journal Article (2 results) (of which Peer Reviewed: 1 results) Presentation (7 results)

  • [Journal Article] Synthesis and Biological Activities of Reveromycin A and Spirofungin A Derivatives2008

    • Author(s)
      Takeshi Shimizu
    • Journal Title

      Bioorg. Med. Chem. Lett. 18(In press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Synthesis and Biological Activities of Reveromycin A and Spirofungin A Derivatives2008

    • Author(s)
      Takeshi Shimizu
    • Journal Title

      Bioorg. Med. Chem. Lett. 18(in press)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 6,6-スピロケタール天然物の合成と活性2008

    • Author(s)
      清水 猛
    • Organizer
      第4回ケミカルバイオロジーシンポジウム
    • Place of Presentation
      熱海
    • Year and Date
      2008-02-07
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] Synthesis and Biological Evaluation of 6, 6-Spiroketal Natural Products2008

    • Author(s)
      Shimizu Takeshi
    • Organizer
      4th RIKEN Symposium on Chemical Biology
    • Place of Presentation
      Atami, Sizuoka
    • Year and Date
      2008-02-07
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] 6,6-スピロケタール天然物の合成と活性2007

    • Author(s)
      清水 猛
    • Organizer
      第49回天然有機化合物討論会
    • Place of Presentation
      札幌
    • Year and Date
      2007-09-21
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] Synthesis and Biological Evaluation of 6, 6-Spiroketal Natural Products2007

    • Author(s)
      Shimizu Takeshi
    • Organizer
      49th Symposium on the Chemistry of Natural Products
    • Place of Presentation
      Sapporo, Hokkaido
    • Year and Date
      2007-09-21
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Synthetic Studies of Reveromycin A : Novel Preparation of the Succinates of Tertiary Alcohols2007

    • Author(s)
      Takeshi Shimizu
    • Organizer
      21st International Congress for Heterocyclic Chemistry
    • Place of Presentation
      Australia, Sydney
    • Year and Date
      2007-07-19
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Synthetic Studies of Reveromycin A : Novel Preparation of the Succinates of Tertiary Alcohols2007

    • Author(s)
      Shimizu Takeshi
    • Organizer
      21st International Congress for Heterocyclic Chemistry
    • Place of Presentation
      Sydney, Australia
    • Year and Date
      2007-07-19
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] Synthetic Studies of Reveromycin A:Novel Preparation of the Succinates of Tertiary Alcohols2007

    • Author(s)
      Takeshi Shimizu
    • Organizer
      21^<st> International Congress for Heterocyclic Chemistry
    • Place of Presentation
      Australia,Sydney
    • Year and Date
      2007-07-19
    • Related Report
      2007 Annual Research Report

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Published: 2006-04-01   Modified: 2016-04-21  

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