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Elucidation of axial chirality in sulfonamide and development of novel medicinal compounds

Research Project

Project/Area Number 16K08326
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Drug development chemistry
Research InstitutionTeikyo University

Principal Investigator

Tabata Hidetsugu  帝京大学, 薬学部, 准教授 (80445634)

Co-Investigator(Kenkyū-buntansha) 夏苅 英昭  新潟薬科大学, 薬学部, 客員研究員 (00334334)
Project Period (FY) 2016-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2018: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2016: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
Keywords軸不斉 / スルホンアミド / スルホンアミド構造 / 軸性キラリティー
Outline of Final Research Achievements

The 5N-arylsulfonyl-1,5-benzodiazepin-2-ones with antiproliferative activity were prepared and successfully separated into the (aR)- and (aS)-atropisomers with extraordinary stability (ΔG‡= ∼130 kJ/mol) by freezing the conformation around the sp2-sp2 axis in an Ar-N(SO2) moiety with a C6-methyl group. Also, by introducing a C3-methyl group (central chirality) into the 1,5-benzodiazepine nucleus, the stereochemistry at the axis was biased to take solely one diastereomer with a relative stereochemistry of (aS*,3S*). The (aS) stereochemistry and the folded form of the molecule were revealed to be important for exerting the antiproliferative activity.

Academic Significance and Societal Importance of the Research Achievements

本研究において、キラリティーの存在が認識されていないスルホンアミド構造をキラリティーの観点から追究・解明し、生物活性との相関を明らかにしたことは、従来の中心不斉に着目した創薬研究に限らず、軸不斉を意識した新たな創薬研究の重要性を周知させるものとなった。スルホンアミド構造を有する医薬品はたいへん多く、スルホンアミドのキラリティーの解明が医薬品の分子設計を変えることに繋がり、より有用性の高い医薬品開発を通じて社会へ大きく貢献するものである。また、中心不斉から始まったキラリティーの概念をより幅広く広げる役割も担っており医薬化学分野だけでなく、基礎的な有機化学分野への波及効果も高いと言える。

Report

(5 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (25 results)

All 2020 2019 2018 2017 2016

All Journal Article (9 results) (of which Peer Reviewed: 8 results,  Acknowledgement Compliant: 3 results,  Open Access: 1 results) Presentation (16 results) (of which Int'l Joint Research: 3 results)

  • [Journal Article] Elucidation of the Active Conformation of Antiproliferative Sulfonamides, 5 N-Arylsulfonyl-1,5-benzodiazepin-2-ones2019

    • Author(s)
      Tabata Hidetsugu、Funaki Kaoru、Tasaka Tomohiko、Oshitari Tetsuta、Takahashi Hideyo、Natsugari Hideaki
    • Journal Title

      The Journal of Organic Chemistry

      Volume: 84 Issue: 24 Pages: 16338

    • DOI

      10.1021/acs.joc.9b02833

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Atropisomeric and conformational properties of 6N-benzoyl-and 6N-p-tosyl-1,6-benzodiazocines: Comparison with those of 1,5-benzodiazepines2019

    • Author(s)
      Tabata, Hidetsugu; Murai, Kazuya: Funaki, Kaoru; Takemae, Chihiro; Tasaka, Tomohiko; Oshitari, Tetsuta; Takahashi, Hideyo; Natsugari, Hideaki.
    • Journal Title

      Heterocycles

      Volume: 99 Issue: 1 Pages: 566

    • DOI

      10.3987/com-18-s(f)55

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Atropisomerism in the 2,3,4,5-Tetrahydro-1 H -1,5-benzodiazepine Nucleus: Effects of Central Chirality at C3 on the N-Mesylation Reaction2018

    • Author(s)
      Tabata, Hidetsugu; Tsuji, Yuka; Yoneda, Tetsuya; Tasaka, Tomohiko; Oshitari, Tetsuta; Takahashi, Hideyo; Natsugari, Hideaki
    • Journal Title

      Synlett

      Volume: 29 Issue: 16 Pages: 2141

    • DOI

      10.1055/s-0037-1609868

    • Related Report
      2018 Research-status Report
    • Peer Reviewed
  • [Journal Article] Tolvaptan-Type Vasopressin Receptor Ligands: Important Role of Axial Chirality in the Active Form2017

    • Author(s)
      Tabata, Hidetsugu; Yoneda, Tetsuya; Oshitari, Tetsuta; Takahashi, Hideyo; Natsugari, Hideaki
    • Journal Title

      Journal of Medicinal Chemistry

      Volume: 60 Issue: 10 Pages: 4503

    • DOI

      10.1021/acs.jmedchem.7b00422

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Catalytic asymmetric S-oxidation of N-benzoyl-1,5-benzothiazepines2017

    • Author(s)
      Makino Kosho、Yoneda Tetsuya、Ogawa Risa、Kanase Yuki、Tabata Hidetsugu、Oshitari Tetsuta、Natsugari Hideaki、Takahashi Hideyo
    • Journal Title

      Tetrahedron Letters

      Volume: 58 Issue: 30 Pages: 2885

    • DOI

      10.1016/j.tetlet.2017.06.021

    • URL

      https://pure.teikyo.jp/en/publications/4bd7ace1-2c4e-4492-b65c-bdc6f6a3d064

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Comprehensive Quantitation Using Two Stable Isotopically Labeled Species and Direct Detection of N-Acyl Moiety of Sphingomyelin2017

    • Author(s)
      Hama K, Fujiwara Y, Tabata H, Takahashi H, Yokoyama K.
    • Journal Title

      Lipids

      Volume: 52 Issue: 9 Pages: 789

    • DOI

      10.1007/s11745-017-4279-5

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Elucidation of the E-Amide Preference of N-Acyl Azoles2017

    • Author(s)
      Takahashi Yuka、Ikeda Hirotaka、Kanase Yuki、Makino Kosho、Tabata Hidetsugu、Oshitari Tetsuta、Inagaki Satoshi、Otani Yuko、Natsugari Hideaki、Takahashi Hideyo、Ohwada Tomohiko
    • Journal Title

      Journal of Organic Chemistry

      Volume: 82 Issue: 21 Pages: 11370

    • DOI

      10.1021/acs.joc.7b01759

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Stereochemistry of N-Benzoyl-5-substituted-1-benzazepines Revisited: Synthesis of the Conformationally Biased Derivatives and Revision of the Reported Structure2016

    • Author(s)
      Tabata, Hidetsugu; Yoneda, Tetsuya; Tasaka, Tomohiko; Ito, Shigekazu; Oshitari, Tetsuta; Takahashi, Hideyo; Natsugari, Hideaki
    • Journal Title

      Journal of Organic Chemistry

      Volume: 81 Pages: 3136-3148

    • Related Report
      2016 Research-status Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Electronic effects on the amide E-/Z-preference of N-benzoyl-carbazole derivatives2016

    • Author(s)
      Kayama, Susumu; Tani, Norihiko; Tabata, Hidetsugu; Oshitari, Tetsuta; Natsugari, Hideaki; Takahashi, Hideyo
    • Journal Title

      Tetrahedron Letters

      Volume: 57 Pages: 2395-2398

    • Related Report
      2016 Research-status Report
    • Acknowledgement Compliant
  • [Presentation] (S)-2-フェニルプロピオン酸塩化物を用いるN-アシル化反応による1,5-ベンゾジアゼピン誘導体の軸不斉選択的合成2020

    • Author(s)
      舟木かおる、中里友亮、田畑 英嗣、髙橋由佳、田坂友彦、高橋秀依、忍足鉄太、夏苅英昭
    • Organizer
      日本薬学会140年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Conformational properties based on the axis of 6N-benzoyl- and 6N-p-tosyl-1,6-benzodiazocines: Comparison with those of 1,5-benzodiazepines2019

    • Author(s)
      Hidetsugu Tabata, Kaoru Funaki, Kazuya Murai, Chihiro Takemae, Tomohiko Tasaka, Tetsuta Oshitari, Hideyo Takahashi, Hideaki Natsugari
    • Organizer
      第27回 国際複素環化学会議 (27th ISHC)
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 1,5-ベンゾジアゼピン誘導体の軸不斉と中心不斉に基づく立体化学2019

    • Author(s)
      舟木かおる、田畑英嗣、高橋由佳、高橋秀依、忍足鉄太、夏苅英昭
    • Organizer
      第78回有機合成化学協会関東支部シンポジウム
    • Related Report
      2019 Annual Research Report
  • [Presentation] 3位にメチル基を持つ5N-スルホニル-1,5-ベンゾジアゼピノン類の立体化学と 癌細胞増殖抑制活性2019

    • Author(s)
      田畑英嗣、辻 侑夏、舟木かおる、米田哲也、田坂友彦、忍足鉄太、 高橋秀依、夏苅英昭
    • Organizer
      日本薬学会139年会
    • Related Report
      2018 Research-status Report
  • [Presentation] 5N-スルホニル-3-メチル-1,5-ベンゾジアゼピン-2-オン類の軸不斉と中心不斉の連動性と癌細胞増殖抑制活性2018

    • Author(s)
      田畑英嗣、辻侑夏、舟木かおる、米田哲也、田坂友彦、忍足鉄太、高橋秀依、夏苅英昭
    • Organizer
      第36回メディシナルケミストリーシンポジウム
    • Related Report
      2018 Research-status Report
  • [Presentation] N-ベンゾイル及びN-スルホニル-1,5-ベンゾジアゼピノン類の軸不斉と6位置換基の効果2018

    • Author(s)
      舟木 かおる、森 瑞希、田畑 英嗣、忍足 鉄太、高橋 秀依、夏苅 英昭
    • Organizer
      日本薬学会第138年会
    • Related Report
      2017 Research-status Report
  • [Presentation] Stereochemistry and biological activity of 5-substituted N-benzoyl-1-benzazepines as vasopressin receptor antagonists2017

    • Author(s)
      Hidetsugu Tabata, Tetsuya Yoneda, Tetsuta Oshitari, Hideyo Takahashi, Hideaki Natsugari
    • Organizer
      29th International Symposium on Chirality
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] N-ベンゾイルおよびN-スルホニル-1,6-ベンゾジアゾシン類の軸不斉に基づく立体化学2017

    • Author(s)
      村井和哉、竹前千尋、田畑英嗣、忍足鉄太、高橋秀依、夏苅英昭
    • Organizer
      第61回日本薬学会関東支部大会
    • Related Report
      2017 Research-status Report
  • [Presentation] N-スルホニル-1,5-ベンゾジアゼピン-2-オン類の軸不斉に基づく立体化学と 癌細胞増殖抑制活性2017

    • Author(s)
      田畑英嗣,米田哲也, 忍足鉄太,高橋秀依,夏苅英昭
    • Organizer
      第35回メディシナルケミストリーシンポジウム
    • Related Report
      2017 Research-status Report
  • [Presentation] 5N-スルホニル-1,5-ベンゾジアゼピン-2-オン類の軸不斉に基づく立体化学と癌細胞増殖抑制活性2017

    • Author(s)
      田畑 英嗣、米田 哲也、忍足 鉄太、高橋 秀依、夏苅 英昭
    • Organizer
      第74回有機合成化学協会新藤支部シンポジウム
    • Related Report
      2017 Research-status Report
  • [Presentation] 1,5-ベンゾジアゼピン類の軸不斉と中心不斉の連動性とバソプレシン受容体拮抗作用2016

    • Author(s)
      田畑英嗣,忍足鉄太,高橋秀依,夏苅英昭
    • Organizer
      第34回メディシナルケミストリーシンポジウム
    • Place of Presentation
      茨城県つくば市 つくば国際会議場
    • Year and Date
      2016-11-30
    • Related Report
      2016 Research-status Report
  • [Presentation] ベンゾアゼピン類の立体化学とバソプレシン受容体拮抗作用2016

    • Author(s)
      田畑 英嗣、忍足 鉄太、高橋 秀依、夏苅 英昭
    • Organizer
      第72回有機合成化学協会関東支部シンポジウム
    • Place of Presentation
      新潟県新潟市 新潟薬科大学新津東キャンパス
    • Year and Date
      2016-11-26
    • Related Report
      2016 Research-status Report
  • [Presentation] N-アシル-1-ベンゾアゼピン誘導体のコンホメーション解析とバソプレシン受容体拮抗作用2016

    • Author(s)
      田畑英嗣、米田哲也、忍足鉄太、高橋秀依、夏苅英昭
    • Organizer
      第42回反応と合成の進歩シンポジウム
    • Place of Presentation
      静岡県静岡市 清水文化会館
    • Year and Date
      2016-11-07
    • Related Report
      2016 Research-status Report
  • [Presentation] 5位に置換基を有するN-ベンゾイル-1-ベンゾアゼピン類の立体化学2016

    • Author(s)
      田畑英嗣、米田哲也、忍足鉄太、高橋秀依、夏苅英昭
    • Organizer
      第109回有機合成シンポジウム
    • Place of Presentation
      東京都目黒区 東京工業大学大岡山キャンパス
    • Year and Date
      2016-06-08
    • Related Report
      2016 Research-status Report
  • [Presentation] 5位に置換基を持つN-アシルベンゾアゼピン誘導体の立体化学とバソプレシン受容体拮抗作用2016

    • Author(s)
      田畑英嗣、米田哲也、忍足鉄太、高橋秀依、夏苅英昭
    • Organizer
      第14回次世代を担う有機化学シンポジウム
    • Place of Presentation
      東京都渋谷区 長井記念ホール
    • Year and Date
      2016-05-27
    • Related Report
      2016 Research-status Report
  • [Presentation] Stereochemistry and biological activity of 5-substituted N-acyl-1-benzazepine derivatives as vasopressin receptor antagonists2016

    • Author(s)
      Hidetsugu Tabata, Tetsuya Yoneda, Tomohiko Tasaka, Tetsuta Oshitari, Hideyo Takahashi, Hideaki Natsugari
    • Organizer
      The 25th French-Japanese Symposium on Medicinal and Fine Chemistry
    • Place of Presentation
      東京都多摩市 京王プラザホテル多摩
    • Year and Date
      2016-05-15
    • Related Report
      2016 Research-status Report
    • Int'l Joint Research

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Published: 2016-04-21   Modified: 2021-02-19  

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