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Synthesis of aminophosphoric acid-containing peptides based on direct asymmetric reaction to iminophosphoric acid peptides

Research Project

Project/Area Number 20K06965
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
Research InstitutionThe University of Tokushima

Principal Investigator

INOKUMA Tsubasa  徳島大学, 大学院医歯薬学研究部(薬学域), 講師 (40541272)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsアミノリン酸 / 異常アミノ酸含有ペプチド / ジアステレオ選択的反応 / インドリル化 / アリール化 / 不斉触媒 / ジアステレオ選択的インドリル化 / 疎水性アンカー / Friedel-Crafts型反応 / ベンゼンスルフェニルイミン / α―アミノリン酸含有ペプチド / ペプチドへの直接的不斉反応 / プロテアーゼ阻害剤
Outline of Research at the Start

キラルα―アミノリン酸を含有するペプチドはプロテアーゼ基質の遷移状態アナログとして機能することによるプロテアーゼ阻害活性が期待される魅力的な化合物群であるがその効率的な合成法は確立されていない。本研究で代表者は多様な側鎖構造を有するキラルα―アミノリン酸含有ペプチドの迅速合成法確立を目指す。側鎖構造を持たないアミノリン酸含有ペプチドを酸化することでイミノリン酸ペプチドとし、代表者が先行研究で確立した『ペプチドへの直接的不斉反応』を適用することで所望のペプチドを合成する。

Outline of Final Research Achievements

I previously developed a methodology for synthesis of non-canonical amino
acid-containing peptide via direct asymmetric reaction to peptidic substrate. In this study, I planned to further optimize the synthetic process along with the apply to the synthesis of peptide containing aminophosphonic acid which can act as an transition state analog of the substrate of protease. Although, the preparation of aminophospnic acid derivatives was not acheived, I succeeded in developing a highly diastereodivergent indolylation of the imino peptides by using the properly selected asymmetric catalyst.

Academic Significance and Societal Importance of the Research Achievements

ペプチドはそのアミノ酸配列に応じて多様な機能を付与できることから近年新たな医薬品候補化合物として注目されている。アミノ酸に類似する構造を有するアミノリン酸は各種加水分解酵素の遷移状態アナログとして機能することからアミノリン酸含有ペプチドは新規医薬品候補物質として期待されている。研究代表者が考案したペプチドへの直接的不斉反応を、アミノリン酸含有ペプチドに適用できるようになれば不斉反応時の求核剤を変更するのみで多様な側鎖構造をアミノリン酸含有ペプチド鎖に迅速に導入できる。そのため、本合成プロセスの反応適用拡大はペプチドを基盤とする創薬研究を推し進める大きな駆動力となる。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (10 results)

All 2023 2022 2021 2020

All Journal Article (7 results) (of which Peer Reviewed: 7 results,  Open Access: 1 results) Presentation (3 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] Remote electronic effect on the N-heterocyclic carbene-catalyzed asymmetric intramolecular Stetter reaction and structural revision of products2023

    • Author(s)
      Inokuma Tsubasa、Iritani Kohei、Takahara Yuki、Sun Chunzhao、Yamaoka Yousuke、Kuwano Satoru、Yamada Ken-ichi
    • Journal Title

      Chemical Communications

      Volume: 59 Issue: 36 Pages: 5375-5378

    • DOI

      10.1039/d3cc00693j

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Preparation of N‐2‐Nitrophenylsulfenyl Imino Peptides and Their Catalyst‐Controlled Diastereoselective Indolylation2022

    • Author(s)
      Inokuma Tsubasa、Masui Kana、Fukuhara Koki、Yamada Ken‐ichi
    • Journal Title

      Chemistry -A European Journal

      Volume: 29 Issue: 8

    • DOI

      10.1002/chem.202203120

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Kinetic Resolution of α‐Hydroxyamide via N‐Heterocyclic Carbene‐Catalyzed Acylation2022

    • Author(s)
      Yamada Ken‐ichi、Yamauchi Akiho、Fujiwara Tatsuya、Hashimoto Keiji、Wang Yinli、Kuwano Satoru、Inokuma Tsubasa
    • Journal Title

      Asian Journal of Organic Chemistry

      Volume: 11 Issue: 10

    • DOI

      10.1002/ajoc.202200452

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Enhanced Molecular Recognition through Substrate-Additive Complex Formation in N-Heterocyclic-Carbene-Catalyzed Kinetic Resolution of α-Hydroxythioamides2022

    • Author(s)
      Wang Yinli、Yamauchi Akiho、Hashimoto Keiji、Fujiwara Tatsuya、Inokuma Tsubasa、Mitani Yuta、Ute Koichi、Kuwano Satoru、Yamaoka Yousuke、Takasu Kiyosei、Yamada Ken-ichi
    • Journal Title

      ACS Catalysis

      Volume: 12 Issue: 10 Pages: 6100-6107

    • DOI

      10.1021/acscatal.2c01579

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Synthesis of Non-canonical Amino Acids and Peptide Containing Them for Establishment of the Template for Drug Discovery2021

    • Author(s)
      Inokuma, T
    • Journal Title

      Chemical and Pharmaceutical Bulletin

      Volume: 69 Issue: 4 Pages: 303-313

    • DOI

      10.1248/cpb.c21-00031

    • NAID

      130008013934

    • ISSN
      0009-2363, 1347-5223
    • Year and Date
      2021-04-01
    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The rationale for stereoinduction in conjugate addition to alkylidenemalonates bearing a menthol-derived chiral auxiliary2021

    • Author(s)
      Yamada, K.; Fujiwara, S.; Inokuma, T.; Sugano, M.; Yamaoka, Y.; Takasu, K.
    • Journal Title

      Tetrahedron

      Volume: 91 Pages: 132220-132220

    • DOI

      10.1016/j.tet.2021.132220

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Mechanistic Support for Intramolecular Migrative Cyclization of Propargyl Sulfones Provided by Catalytic Asymmetric Induction with a Chiral Counter Cation Strategy.2021

    • Author(s)
      Yamasaki, K.; Yamauchi, A.; Inokuma, T.; Miyakawa, Y.; Wang, Y.; Oriez, R.; Yamaoka, Y.; Takasu, K.; Tanaka, N.; Kashiwada, Y.; Yamada, K.
    • Journal Title

      Asian J. Org. Chem.

      Volume: - Issue: 7 Pages: 1828-1834

    • DOI

      10.1002/ajoc.202100274

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Presentation] Diastereoselective indolylation of N-2-nitrophenylsulfenyl iminopeptide for the synthesis of a-indolylglycine-containing peptide2022

    • Author(s)
      Tsubasa Inokuma, Kana Masui, Masaya Denda, Akira Otaka, Ken-ichi Yamada
    • Organizer
      第59回ペプチド討論会
    • Related Report
      2022 Annual Research Report
  • [Presentation] N-Sulfur-substituted imines as a stable precursor for asymmetric synthesis of α-amino phosphonic acid derivatives2022

    • Author(s)
      Tsubasa Inokuma, Takuya Sakakibara, Ken-ichi Yamada
    • Organizer
      The 12th International Conference on the Biology, Chemistry and Therapeutic Applications of Nitric Oxide The 22nd Annual Scientific Meeting of the Nitric Oxide Society of Japan
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] イミノペプチドへのインドール求核剤の不斉付加反応の開発2020

    • Author(s)
      猪熊 翼、増井 香奈、西田 航大、重永 章、大髙 章、山田 健一
    • Organizer
      第49回複素環化学討論会
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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