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Synthetic and medicinal studies on bioactive indole alkaloids based on direct construction of polycyclic ring systems

Research Project

Project/Area Number 17H03971
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Chemical pharmacy
Research InstitutionKyoto University

Principal Investigator

Hiroaki Ohno  京都大学, 薬学研究科, 教授 (30322192)

Co-Investigator(Kenkyū-buntansha) 井貫 晋輔  京都大学, 薬学研究科, 准教授 (70736272)
Project Period (FY) 2017-04-01 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000)
Fiscal Year 2020: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000)
Fiscal Year 2019: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2018: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2017: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Keywords天然物合成 / 連続反応 / アルカロイド / 金触媒 / 創薬 / 多環式芳香族化合物 / インドール / 有機化学
Outline of Final Research Achievements

This is a basic study for natural-product-based drug discovery, conducting the direct construction of heterocyclic compounds and synthesis of biologically-active indole alkaloids. We have developed the gold-catalyzed cascade cyclization reactions for the synthesis of fused carbazoles using azido-alkynes, direct construction of the akuammiline alkaloid scaffold using alkynyl indoles, and the synthesis of acenaphthenes using allenynes. Furthermore, we succeeded in total synthesis of dictyodendrins, construction of the fused indole scaffolds found in aspidophylline A and ergot alkaloids, and obtained promising biologically active compounds.

Academic Significance and Societal Importance of the Research Achievements

これまでの創薬研究に用いられてきた化合物ライブラリーの構築は、アミド結合やクロスカップリング等のsp2炭素を利用した結合形成反応に頼ることが多かったため、化合物空間が平面的な低分子に偏りやすかった。そのようなライブラリーから有望なヒット化合物を見出すことが益々困難となっている現状から、比較的複雑な基本骨格を有する天然物型化合物の重要性が再認識されている。一方で、複雑な構造を有する天然物は基本骨格の構築に多段階を要するため、これが創薬展開の大きな障壁となっている。本研究は、天然物創薬研究におけるこれらの課題の解決を図るものとして、学術的および社会的に重要であると考えている。

Report

(5 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Annual Research Report
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (47 results)

All 2021 2020 2019 2018 2017 Other

All Journal Article (15 results) (of which Peer Reviewed: 15 results) Presentation (31 results) (of which Int'l Joint Research: 14 results,  Invited: 9 results) Remarks (1 results)

  • [Journal Article] Nonbiomimetic total synthesis of indole alkaloids using alkyne-based strategies2021

    • Author(s)
      Ohno Hiroaki、Inuki Shinsuke
    • Journal Title

      Organic & Biomolecular Chemistry

      Volume: 19 Issue: 16 Pages: 3551-3568

    • DOI

      10.1039/d0ob02577a

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Total Synthesis of Dictyodendrins A-F by the Gold‐Catalyzed Cascade Cyclization of Conjugated Diyne with Pyrrole2020

    • Author(s)
      Matsuoka Junpei、Inuki Shinsuke、Matsuda Yuka、Miyamoto Yoichi、Otani Mayumi、Oka Masahiro、Oishi Shinya、Ohno Hiroaki
    • Journal Title

      Chemistry - A European Journal

      Volume: 26 Issue: 49 Pages: 11150-11157

    • DOI

      10.1002/chem.202001950

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Total Synthesis of (+)-Polyoxamic Acid via Visible-Light-Mediated Photocatalytic β-Scission and 1,5-Hydrogen Atom Transfer of Glucose Derivative2020

    • Author(s)
      Matsuoka Takuro、Inuki Shinsuke、Miyagawa Takashi、Oishi Shinya、Ohno Hiroaki
    • Journal Title

      The Journal of Organic Chemistry

      Volume: 85 Issue: 12 Pages: 8271-8278

    • DOI

      10.1021/acs.joc.0c00910

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Total Synthesis of Zephycarinatines via Photocatalytic Reductive Radical ipso ‐Cyclization2020

    • Author(s)
      Takeuchi Haruka、Inuki Shinsuke、Nakagawa Kohei、Kawabe Takaaki、Ichimura Atsuhiko、Oishi Shinya、Ohno Hiroaki
    • Journal Title

      Angewandte Chemie International Edition

      Volume: 59 Issue: 47 Pages: 21210-21215

    • DOI

      10.1002/anie.202009399

    • NAID

      120006898144

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Gold(I)-Catalyzed Cascade Cyclization of Anilines with Diynes: Controllable Formation of Eight-Membered Ring-Fused Indoles and Propellane-Type Indolines2020

    • Author(s)
      A. Yamaguchi, S. Inuki, Y. Tokimizu, S. Oishi, H. Ohno
    • Journal Title

      J. Org. Chem.

      Volume: 85 Issue: 4 Pages: 2543-2559

    • DOI

      10.1021/acs.joc.9b03256

    • NAID

      120006817609

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Gold(I)-Catalyzed Cascade Cyclization Reactions of Allenynes for the Synthesis of Fused Cyclopropanes and Acenaphthenes2019

    • Author(s)
      T. Ikeuchi, S. Inuki, S. Oishi, H. Ohno
    • Journal Title

      Angew. Chem. Int. Ed.

      Volume: 58 Issue: 23 Pages: 7792-7796

    • DOI

      10.1002/anie.201903384

    • NAID

      120006634622

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Construction of Quaternary Carbon Stereocenter of α-Tertiary Amine through Remote C-H Functionalization of Tris Derivatives: Enantioselective Total Synthesis of Myriocin2019

    • Author(s)
      Miyagawa Takashi、Inuki Shinsuke、Oishi Shinya、Ohno Hiroaki
    • Journal Title

      Organic Letters

      Volume: 21 Issue: 14 Pages: 5485-5490

    • DOI

      10.1021/acs.orglett.9b01778

    • NAID

      120006719313

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Construction of the Pyrrolo[2,3-d]carbazole Core of Spiroindoline Alkaloids by Gold-Catalyzed Cascade Cyclization of Ynamide2019

    • Author(s)
      J. Matsuoka, H. Kumagai, S. Inuki, S. Oishi, H. Ohno
    • Journal Title

      J. Org. Chem.

      Volume: 84 Issue: 14 Pages: 9358-9363

    • DOI

      10.1021/acs.joc.9b01149

    • NAID

      120006708241

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Introduction of a Polar Functional Group to the Lipid Tail of 4-<i>epi</i>-Jaspine B Affects Sphingosine Kinase Isoform Selectivity2018

    • Author(s)
      S. Inuki, T. Miyagawa, S. Oishi, H. Ohno
    • Journal Title

      Chemical and Pharmaceutical Bulletin

      Volume: 66 Issue: 9 Pages: 866-872

    • DOI

      10.1248/cpb.c18-00366

    • NAID

      130007479591

    • ISSN
      0009-2363, 1347-5223
    • Year and Date
      2018-09-01
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Synthesis of Jaspine B Regioisomers through Palladium-Catalyzed Stereoselective Tetrahydrofuran Formation: Insight into the Ligand Recognition of Sphingosine Kinases2018

    • Author(s)
      Miyagawa, S. Inuki, M. Honda, S. Nakamura, I. Nakanishi, N. Fujii, S. Oishi, H. Ohno
    • Journal Title

      Tetrahdron

      Volume: 74 Issue: 15 Pages: 1802-1809

    • DOI

      10.1016/j.tet.2018.02.042

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Gold(I)-Catalyzed Oxidative Cascade Cyclization of 1,4-Diyn-3-ones for the Construction of Tropone-Fused Furan Scaffolds2018

    • Author(s)
      N. Hamada, A. Yamaguchi, S. Inuki, S. Oishi, H. Ohno
    • Journal Title

      Org. Lett.

      Volume: 20 Issue: 15 Pages: 4401-4405

    • DOI

      10.1021/acs.orglett.8b01524

    • NAID

      120006634623

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Direct Synthesis of Aryl-Annulated [c]Carbazoles by Gold(I)-Catalysed Cascade Reaction of Azide-Diynes and Arenes2018

    • Author(s)
      Y. Kawada, S. Ohmura, M. Kobayashi, W. Nojo, M. Kondo, Y. Matsuda, J. Matsuoka, S. Inuki, S. Oishi, C. Wang, T. Saito, M. Uchiyama, T. Suzuki, H. Ohno
    • Journal Title

      Chem. Sci.

      Volume: 9 Pages: 8416-8425

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Identification of Selective Inhibitors of Sphingosine Kinases 1 and 2 through a Structure-Activity Relationship Study of 4-epi-Jaspine B2017

    • Author(s)
      H. Ohno, M. Honda, N. Hamada, J. Miyagaki, A. Iwata, K. Otsuki, T. Maruyama, S. Nakamura, I. Nakanishi, S. Inuki, N. Fujii, S. Oishi
    • Journal Title

      Bioorg. Med. Chem.

      Volume: 25 Issue: 12 Pages: 3046-3052

    • DOI

      10.1016/j.bmc.2017.03.059

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Total Synthesis of Dictyodendrins by the Gold-Catalyzed Cascade Cyclization of Conjugated Diynes with Pyrroles2017

    • Author(s)
      J. Matsuoka, Y. Matsuda, Y. Kawada, S. Oishi, H. Ohno
    • Journal Title

      Angew. Chem. Int. Ed.

      Volume: 56 Issue: 26 Pages: 7444-7448

    • DOI

      10.1002/anie.201703279

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Gold-Catalyzed Cascade Reaction of Skipped Diynes for the Construction of a Cyclohepta[b]pyrrole Scaffold2017

    • Author(s)
      N. Hamada, Y. Yoshida, S. Oishi, H. Ohno
    • Journal Title

      Org. Lett.

      Volume: 19 Pages: 3875-3878

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Presentation] 生合成を模倣しない戦略によるインドールアルカロイドの全合成研究2021

    • Author(s)
      大野浩章
    • Organizer
      日本薬学会第141年会
    • Related Report
      2020 Annual Research Report
    • Invited
  • [Presentation] 金触媒連続環化反応を基盤としたPicrinineの合成研究2021

    • Author(s)
      橋本直季, 田口淳一, 大石真也, 井貫晋輔, 大野浩章
    • Organizer
      日本薬学会第141年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 金触媒を用いたアルキンのヒドロアリール化による縮環型インドレニン骨格の構築2021

    • Author(s)
      島恭平, 大石真也, 井貫晋輔, 大野浩章
    • Organizer
      日本薬学会第141年会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 可視光レドックス触媒によるβ開裂・C(sp3)-C(sp3)1,5-HAT連続反応を利用した(+)-polyoxamic acidの全合成2020

    • Author(s)
      松岡巧朗, 井貫晋輔, 宮川貴吏, 大石真也, 大野浩章
    • Organizer
      第62回天然有機化合物討論会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 金触媒を用いたアレンインの連続環化反応による含窒素複素環骨格の構築2020

    • Author(s)
      小松紘樹, 池内貴哉, 大石真也, 井貫晋輔, 大野浩章
    • Organizer
      第70回日本薬学会関西支部大会
    • Related Report
      2020 Annual Research Report
  • [Presentation] 可視光レドックス触媒を用いたラジカルipso環化反応を鍵とするZephycarinatine CおよびDの全合成2020

    • Author(s)
      井貫晋輔, 竹内春佳, 中川航平, 川邊隆彰, 市村敦彦, 大石真也, 大野浩章
    • Organizer
      反応と合成の進歩2020特別企画シンポジウム
    • Related Report
      2020 Annual Research Report
  • [Presentation] Total synthesis of dictyodendrins by the gold-catalyzed cascade cyclization of conjugated diynes with pyrroles2019

    • Author(s)
      Junpei Matsuoka, Yuka Matsuda, Yuiki Kawada, Shinsuke Inuki, Shinya Oishi, Hiroaki Ohno
    • Organizer
      The 11th Seoul-Kyoto-Osaka Joint Symposium on Pharmaceutical Sciences for Young Scientists
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Gold-Catalyzed Cascade Cyclization Reactions via C-H Bond Cleavage2019

    • Author(s)
      Hiroaki Ohno
    • Organizer
      The 47th Naito Conference
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Gold-Catalyzed C-C bond Formation and Its Application to Alkaloid Synthesis2019

    • Author(s)
      Hiroaki Ohno
    • Organizer
      Technische Universitat Wien Special Lecture
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 金触媒を用いた分子内連続環化反応を基盤としたAspidophylline Aの全合成研究2019

    • Author(s)
      田口淳一, 奥村怜司, 大原礼子, 井貫晋輔, 大石真也, 大野浩章
    • Organizer
      第39回有機合成若手セミナー
    • Related Report
      2019 Annual Research Report
  • [Presentation] Gold-Catalyzed Cascade Cyclization of Anilines with Diynes: Controllable Formation of Eight-Membered Ring Fused Indoles and Propellane-Type Indolines2019

    • Author(s)
      Ayuta Yamaguchi, Shinsuke Inuki, Yusuke Tokimizu, Shinya Oishi, Hiroaki Ohno
    • Organizer
      27th International Society of Heterocyclic Chemistry Congress
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Synthetic Study of Aspidophylline A Based on Gold(I)-Catalyzed Cascade Cyclization2019

    • Author(s)
      Junichi Taguchi, Reiji Okumura, Ayako Ohara, Shinsuke Inuki, Shinya Oishi and Hiroaki Ohno
    • Organizer
      27th International Society of Heterocyclic Chemistry Congress
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Total Synthesis of Dictyodendrins by the Gold-Catalyzed Cascade Cyclization of Conjugated Diynes with Pyrroles2019

    • Author(s)
      Junpei Matsuoka, Yuka Matsuda, Yuiki Kawada, Shinsuke Inuki, Shinya Oishi, Hiroaki Ohno
    • Organizer
      27th International Society of Heterocyclic Chemistry Congress
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Dictyodendrin 類の多様性志向型全合成2019

    • Author(s)
      松岡純平、松田優佳、川田惟樹、井貫晋輔、大石真也、大野浩章
    • Organizer
      第61回天然有機化合物討論会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Gold-Catalyzed Cascade Cyclization for Fused Ring Construction2019

    • Author(s)
      Hiroaki Ohno
    • Organizer
      The 8th Japanese-Sino Symposium on Organic Chemistry for Young Scientists
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Controllable Formation of Oxocine-Fused Indoles and Propellane-Type Indolines via Gold-Catalyzed Cascade Cyclization2019

    • Author(s)
      Ayuta Yamaguchi, Shinsuke Inuki, Yusuke Tokimizu, Shinya Oishi, Hiroaki Ohno
    • Organizer
      The 8th Japanese-Sino Symposium on Organic Chemistry for Young Scientists
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Gold-Catalyzed Cascade Cyclization of Alkynyl Tryptophol Derivatives: Synthetic Strategy for Aspidophylline A2019

    • Author(s)
      Junichi Taguchi, Reiji Okumura, Ayako Ohara, Shinsuke Inuki, Shinya Oishi, Hiroaki Ohno
    • Organizer
      The 8th Japanese-Sino Symposium on Organic Chemistry for Young Scientists
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Dictyodendrin 類の多様性志向型全合成2019

    • Author(s)
      松岡純平、松田優佳、川田惟樹、井貫晋輔、大石真也、大野浩章
    • Organizer
      第69回日本薬学会関西支部総会・大会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 金触媒連続環化反応を基盤としたAspidophylline Aの全合成研究2019

    • Author(s)
      田口淳一、奥村怜司、大原礼子、井貫晋輔、大石真也、大野浩章
    • Organizer
      日本薬学会第139年会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 金触媒を用いた複素環骨格の構築とアルカロイドの全合成2018

    • Author(s)
      大野浩章
    • Organizer
      第53回天然物化学談話会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Synthesis of Fused Cyclopropanes via Gold-Catalyzed Cascade Cyclization of Allenynes2018

    • Author(s)
      池内貴哉、井貫晋輔、大石真也、大野浩章
    • Organizer
      JGP Chem & ChemEn International Workshop: Sustainability-Oriented Organic Synthesis
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Synthetic Study of Akuammiline Alkaloids Based on Gold(I)-Catalyzed Cascade Cyclization2018

    • Author(s)
      田口淳一、奥村怜司、大原礼子、井貫晋輔、大石真也、大野浩章
    • Organizer
      JGP Chem & ChemEn International Workshop: Sustainability-Oriented Organic Synthesis
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 天然物骨格一挙構築法の開発と応用2018

    • Author(s)
      大野浩章
    • Organizer
      京大テックフォーラム
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Dictyodendrin類の多様性志向型全合成2018

    • Author(s)
      松岡純平、松田優佳、川田惟樹、大石真也、大野浩章
    • Organizer
      「有機合成化学を起点とするものづくり戦略」 最終シンポジウム
    • Related Report
      2018 Annual Research Report
  • [Presentation] Gold-Catalyzed C-C bond Formation and Its Application to Alkaloid Synthesis2018

    • Author(s)
      Hiroaki Ohno
    • Organizer
      1st NCTU Conference on Advanced Organic Synthesis
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Direct Construction of Fused Nitrogen Heterocycles by Gold-Catalyzed Cascade Cyclizations2017

    • Author(s)
      Hiroaki Ohno
    • Organizer
      Nordic/Kyoto OMCOS 2017
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 金触媒によるアルカロイド型骨格の構築と全合成研究2017

    • Author(s)
      大野浩章
    • Organizer
      第37回有機合成若手セミナー
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] Total Synthesis of Dictyodendrins by the Gold-Catalyzed Intermolecular Cascade Cyclization of Conjugated Diynes with Pyrroles2017

    • Author(s)
      Junpei Matsuoka, Yuka Matsuda, Yuiki Kawada, Shinya Oishi, Hiroaki Ohno
    • Organizer
      254th ACS National Meeting
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 金触媒を用いた分子内連続環化反応を基盤としたAspidophylline Aの全合成研究2017

    • Author(s)
      奥村怜司、大原礼子、熊谷洋、大石真也、大野浩章
    • Organizer
      第59回天然有機化合物討論会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Dictyodendrin類の網羅的全合成と誘導体の活性評価2017

    • Author(s)
      松岡純平,松田優佳,川田惟樹, 大石真也, 大野浩章
    • Organizer
      第43回反応と合成の進歩シンポジウム
    • Related Report
      2017 Annual Research Report
  • [Presentation] 金触媒を用いたスキップジインの連続反応によるシクロヘプタ[b]ピロール骨格の構築2017

    • Author(s)
      濱田直佳,吉田勇介,大石真也, 大野浩章
    • Organizer
      第43回反応と合成の進歩シンポジウム
    • Related Report
      2017 Annual Research Report
  • [Remarks] 研究室ホームページ

    • URL

      http://www.pharm.kyoto-u.ac.jp//seizo/

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report 2018 Annual Research Report 2017 Annual Research Report

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Published: 2017-04-28   Modified: 2022-01-27  

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