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Natural Product Hybrids : Design, Synthesis and Evaluation of Novel Antimicrobial Agents

Research Project

Project/Area Number 21890262
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeSingle-year Grants
Research Field Drug development chemistry
Research InstitutionTokyo University of Pharmacy and Life Science

Principal Investigator

YAKUSHIJI Fumika  Tokyo University of Pharmacy and Life Science, 薬学部, 助教 (40548476)

Project Period (FY) 2009 – 2010
Project Status Completed (Fiscal Year 2010)
Budget Amount *help
¥2,652,000 (Direct Cost: ¥2,040,000、Indirect Cost: ¥612,000)
Fiscal Year 2010: ¥1,261,000 (Direct Cost: ¥970,000、Indirect Cost: ¥291,000)
Fiscal Year 2009: ¥1,391,000 (Direct Cost: ¥1,070,000、Indirect Cost: ¥321,000)
Keywordsハイブリッド / 抗菌活性 / RNAポリメラーゼ / Holothin / Myxopyronin / Thiomarinol / 機能性分子 / 分子モデリング
Research Abstract

1)Previously, the total syntheses of hybrid type natural products ‘thiomarinols' were accomplished by author. Thiomarinols were found to exhibit potent antimicrobial activity, which came from hybrid structure : pseudomonic acid part and holothin part. Based on the synthetic pathway, hybrid type derivatives as antimicrobial agents were designed and synthesized. The structure-activity relationship studies and optimization are now in progress.
2)Myxopyronins were isolated from Myxococcus fulvus Mx f50 and found to exhibit antimicrobial activity, which inhibition mechanism was reported as a novel pathway. However, myxopyronin revealed high lipophilicity and limited membrane permeability which are inadequate aspects for a drug. This time, design and synthesis of novel hybrid-type derivatives of myxopyronins with the strategy of linking holothin part, which included in thiomarionols, were attempted to improve lipophilicity and cell permeability for broad antibacterial spectrum. Synthesized derivatives were evaluated as antimicrobial agents, and some derivatives showed more potent activity than myxopyronins against gram-positive bacterias on minimal inhibitory concentration (MIC) results. According to this hybrid strategy, novel antimicrobial derivatives were obtained and structural optimization is now in progress.

Report

(3 results)
  • 2010 Annual Research Report   Final Research Report ( PDF )
  • 2009 Annual Research Report
  • Research Products

    (24 results)

All 2011 2010 2009

All Journal Article (4 results) (of which Peer Reviewed: 4 results) Presentation (17 results) Patent(Industrial Property Rights) (3 results) (of which Overseas: 1 results)

  • [Journal Article] Tubulin photoaffinity labeling study with a plinabulin chemical probe possessing a biotin tag at the oxazole2011

    • Author(s)
      Yamazaki Y., Kido Y., Hidaka K., Yasui H., Kiso Y., Yakushiji F., Hayashi Y.
    • Journal Title

      Bioorg.Med.Chem. 19

      Pages: 595-602

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Tubulin photoaffinity labeling study with a plinabulin chemical probe possessing a biotin tag at the oxazole2011

    • Author(s)
      Yamazaki, Y., Kido, Y., Hidaka, K., Yasui, H., Kiso, Y., Yakushiji, F., Hayashi, Y.
    • Journal Title

      Bioorganic Medicinal Chemistry

      Volume: 19 Pages: 595-602

    • Related Report
      2010 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Total Synthesis of (+)-Negamycin and Its 5-epi-Derivative2010

    • Author(s)
      Nishiguchi S., Sydnes O.M., Taguchi A., Regnier T., Kajimoto T., Node M., Yamazaki Y., Yakushiji F., Kiso Y., Hayashi Y.
    • Journal Title

      Tetrahedron 66

      Pages: 314-320

    • Related Report
      2010 Final Research Report
    • Peer Reviewed
  • [Journal Article] Total Synthesis of (+)-Negamycin and Its 5-epi-Derivative2010

    • Author(s)
      Shigenobu Nishiguchi, Magne O.Sydnes, Akihiro Taguchi, Thomas Regnier, Tetsuya Kajimoto, Manabu Node, Yuri Yamazaki, Fumika Yakushiji, Yoshiaki Kiso, Yoshio Hayashi
    • Journal Title

      Tetrahedron 66

      Pages: 314-320

    • Related Report
      2009 Annual Research Report
    • Peer Reviewed
  • [Presentation] ハイブリッド型ミキソピロニン類縁体による新世代抗菌活性剤創製研究2011

    • Author(s)
      薬師寺文華,岡本玲子,久能佑樹,宮本裕子,山崎有理,林良雄
    • Organizer
      第131回日本薬学会年会
    • Place of Presentation
      静岡
    • Related Report
      2010 Annual Research Report 2010 Final Research Report
  • [Presentation] Huisgen反応を利用した血管遮断剤Plinabulin水溶性プロドラッグの創製2011

    • Author(s)
      田中達也,薬師寺文華,岩橋孝祐,山崎有理,林良雄
    • Organizer
      第131回日本薬学会年会
    • Place of Presentation
      静岡
    • Related Report
      2010 Annual Research Report 2010 Final Research Report
  • [Presentation] 固相担持型SH基特異的ビオチニル化試薬の合成と低分子化合物への効率的ビオチン標識2011

    • Author(s)
      足立久美, 福元謙太郎, 山崎有理, 薬師寺文華, 林良雄
    • Organizer
      第131回日本薬学会年会
    • Place of Presentation
      静岡
    • Related Report
      2010 Annual Research Report
  • [Presentation] 分子平面性を強化したDidehydro Tryprostatin誘導体の合成とその生物活性2011

    • Author(s)
      篠崎雄希, 山本美彦, 嶽野遙, 山崎有理, 薬師寺文華, 林良雄
    • Organizer
      第131回日本薬学会年会
    • Place of Presentation
      静岡
    • Related Report
      2010 Annual Research Report
  • [Presentation] 新世代抗菌剤開発を指向したハイブリッド型ミキソピロニン類縁体の合成研究2010

    • Author(s)
      薬師寺文華,岡本玲子,山崎有理,林良雄
    • Organizer
      第29回メディシナルケミストリーシンポジウム
    • Place of Presentation
      京都
    • Related Report
      2010 Annual Research Report 2010 Final Research Report
  • [Presentation] 微小管重合阻害剤Plinabulinにおける水溶性プロドラッグの創製2010

    • Author(s)
      薬師寺文華,田中達也,岩橋孝祐,山崎有理,林良雄
    • Organizer
      第29回メディシナルケミストリーシンポジウム
    • Place of Presentation
      京都
    • Related Report
      2010 Annual Research Report 2010 Final Research Report
  • [Presentation] First Total Syntheses of Thiomarinols A and B'2010

    • Author(s)
      Yakushiji F., Yoshida M., Maddaluno J., Hayashi Y., Shishido K.
    • Organizer
      18th IUPAC International Conference on Organic Synthesis
    • Place of Presentation
      Bergen, Norway
    • Related Report
      2010 Final Research Report
  • [Presentation] 「ハイブリッド型ミキソピロニン類縁体の合成研究2010

    • Author(s)
      薬師寺文華,岡本玲子,山崎有理,林良雄
    • Organizer
      日本薬学会第130年会
    • Place of Presentation
      岡山
    • Related Report
      2010 Final Research Report
  • [Presentation] Total Synthesis of Thiomarinols A and B'2010

    • Author(s)
      Yakushiji F., Yoshida M., Maddaluno J., Hayashi Y., Shishido K.
    • Organizer
      ACS Spring 2010 National Meeting & Exposition
    • Place of Presentation
      San Francisco, USA
    • Related Report
      2010 Final Research Report
  • [Presentation] 新世代抗菌剤開発を目的としたハイブリッド型ミキソピロニン誘導体合成研究2010

    • Author(s)
      薬師寺文華, 岡本玲子, 山崎有理, 林良雄
    • Organizer
      第9回国際バイオEXPO
    • Place of Presentation
      東京
    • Related Report
      2010 Annual Research Report
  • [Presentation] First Total Syntheses of Thiomarinols A and B2010

    • Author(s)
      Fumika Yakushiji, Masahiro Yoshida, Jacques Maddaluno, Yoshio Hayashi, Kozo Shishido
    • Organizer
      18th IUPAC International Conference on Organic Synthesis
    • Place of Presentation
      ノルウェー、ベルゲン
    • Related Report
      2010 Annual Research Report
  • [Presentation] Total Synthesis of Thiomarinols A and B2010

    • Author(s)
      Fumika Yakushiji, Masahiro Yoshida, Jacques Maddaluno, Yoshio Hayashi, Kozo Shishido
    • Organizer
      ACS Spring 2010 National Meeting & Exposition
    • Place of Presentation
      San Francisco, USA
    • Related Report
      2009 Annual Research Report
  • [Presentation] ハイブリッド型ミキソピロニン類縁体の合成研究2010

    • Author(s)
      薬師寺文華, 岡本玲子, 山崎有理, 林良雄
    • Organizer
      日本薬学会第130年会
    • Place of Presentation
      岡山
    • Related Report
      2009 Annual Research Report
  • [Presentation] ポリケチド由来生理活性天然物の全合成研究2009

    • Author(s)
      薬師寺文華
    • Organizer
      関東ペプチド研究会
    • Place of Presentation
      東京医科歯科大学
    • Year and Date
      2009-05-26
    • Related Report
      2009 Annual Research Report
  • [Presentation] チオマリノールA及びBの全合成2009

    • Author(s)
      薬師寺文華, 吉田昌裕, Jacques Maddaluno, 林良雄, 宍戸宏造
    • Organizer
      第35回反応と合成の進歩シンポジウム
    • Place of Presentation
      金沢
    • Related Report
      2010 Final Research Report 2009 Annual Research Report
  • [Presentation] Synthesis of (+)-Negamycin and Derivatives2009

    • Author(s)
      Yakushiji F., Nishiguchi S., Sydnes O.M., Taguchi A., Regnier T., Kajimoto T., Node M., Kiso Y., Yamazaki Y., Hayashi Y.
    • Organizer
      3^<rd> Asia-Pasific International Peptide Synposium
    • Place of Presentation
      Jeju, KOREA
    • Related Report
      2010 Final Research Report
  • [Presentation] Synthesis of(+)-Negamycin and Derivatives2009

    • Author(s)
      Fumika Yakushiji, Shigenobu Nishiguchi, Magne O.Sydnes, Akihiro Taguchi, Thomas Regnier, Tetsuya Kajimoto, Manabu Node, Yoshiaki Kiso, Yuri Yamazaki, Yoshio Hayashi
    • Organizer
      3^<rd> Asia-Pasific International Peptide Synposium
    • Place of Presentation
      Jeju, KOREA
    • Related Report
      2009 Annual Research Report
  • [Patent(Industrial Property Rights)] ミキソピロニン誘導体含有抗菌剤2011

    • Inventor(s)
      薬師寺文華
    • Industrial Property Rights Holder
      薬師寺文華,林良雄
    • Industrial Property Number
      2011-070428
    • Filing Date
      2011-03-28
    • Related Report
      2010 Final Research Report
  • [Patent(Industrial Property Rights)] ミキソピロニン誘導体含有抗菌剤2011

    • Inventor(s)
      薬師寺文華
    • Industrial Property Rights Holder
      薬師寺文華、林良雄
    • Filing Date
      2011-03-31
    • Related Report
      2010 Annual Research Report
  • [Patent(Industrial Property Rights)] Plinabulin Prodrug Analogs and Therapeutic Uses Thereof2010

    • Inventor(s)
      薬師寺文華、林良雄
    • Industrial Property Rights Holder
      Yakushiji, F.; Hayashi, Y.; Yamazaki, Y.; Hironari, T.; Lloyd, K.; Reisman, J.; Palladino, M.; Melnick, E.R.
    • Filing Date
      2010-09-23
    • Related Report
      2010 Annual Research Report
    • Overseas

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Published: 2009-04-01   Modified: 2016-04-21  

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