Synthetic study of naturally occurring type III secretion system inhibitors towards the creation of non-microbial anti-infective agent

• Project/Area Number: 19K16318
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: Kitasato University
• Principal Investigator: Noguchi Yoshihiko 北里大学, 感染制御科学府, 特任助教 (00758170)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 非抗菌的坑感染症薬 / III型分泌機構 / 収束的全合成 / ポリエン / cis-テトラヒドロフラン / ピリドン / 感染防御薬 / カスケード反応 / 非抗菌的感染症治療薬 / III型分泌装置

Outline of Research at the Start

病原性細菌の感染機構や病原性発現機構を標的とした薬剤は、抗菌活性を示さない新たな感染症治療薬になると期待される。北里生命科学研究所では新たな創薬標的として、グラム陰性病原性細菌に特徴的な病原因子移行システム「III型分泌装置(T3SS)」に着目し、微生物培養液からT3SSを阻害する化合物の探索を行ってきた。その結果、オーロドックス類が新たにT3SS阻害活性を示すことを見出した。応募者は本化合物群の構造及び活性に注目し、オーロドックス類の収束的全合成を確立ならびに全合成手法を用いて重要なファーマコフォアの探索や抗菌活性とT3SS阻害活性の分離の検証を行い、新たな感染防御薬の創製を指向する。

Outline of Final Research Achievements

Aurodox was found to exhibit potent activity against type III secretion system of pathogenic bacteria without affecting growth in vitro. Structural features are unsaturated ketone connected pyridine fragment, tetra-substituted cis-tetrahydrofuran and highly functionalized pyranose moiety. Due to its unique biological activity and intriguing structure, we have been focusing on its total synthesis towards discovery of non-microbial anti-infective agent. Herein, we report the construction of the highly functionalized pyranose moiety utilizing Evans aldol and intramolecular epoxide opening reaction. In addition, we achieved pyridine fragment by using 1,2-addition.

Academic Significance and Societal Importance of the Research Achievements

オーロドックスの単離から50年近くが経過しているが、化学合成の報告は1985年の1例のみである。先に報告された既知の合成ルートでは、多様な誘導体を簡便かつ効率的に取得することは困難であったため、新たな化学合成法の確立が必須であったため、本研究では既存の手法よりも単工程で各骨格を供給できる合成ルートの確立を目指した。更に本合成ルートの確立は、高T3SS阻害活性化合物の探索など創薬研究に展開できる。
病原性細菌の感染機構や病原性発現機構を標的とした薬剤は抗菌活性を示すことなく、感染源若しくは病原性因子移行のみを阻害する。故に薬剤耐性菌(AMR)が出現しない新たな感染症治療薬になると期待される。

Research Products

• [Journal Article] Towards the total synthesis of aurodox: preparation of the key hemiacetal-lactone (2021)
  • Author(s): Motoyoshi Ohara, Akari Ikeda, Asuka Nakajuma, Takanori Ono, Yoshihiko Noguchi,Akito Watanabe, Tomoyasu Hirose, Toshiaki Sunazuka
  • Journal Title: Tetrahedron Letters Volume: 66 Pages: 152799-152799
  • DOI: 10.1016/j.tetlet.2020.152799
  • Peer Reviewed
• [Journal Article] Unified enantioselective total synthesis of 3,6-dioxygenated diketopiperazine natural products, diatretol and lepistamides A, B and C (2021)
  • Author(s): Shu Takahashi, Aoi Kimishima, Tomoyasu Hirose, Takeshi Yamada, Akihiro Sugawara, Tatsuya Shirahata, Yoshihiko Noguchi, Masato Iwatsuki, Rei Hokari, Aki Ishiyama, Yoshinori Kobayashi, Toshiaki Sunazuka
  • Journal Title: Tetrahedron Letters Volume: 67 Pages: 152895-152895
  • DOI: 10.1016/j.tetlet.2021.152895
  • Peer Reviewed
• [Journal Article] Thioporidiols A and B: Two New Sulfur Compounds Discovered by Molybdenum-Catalyzed Oxidation Screening from Trichoderma polypori FKI-7382 (2020)
  • Author(s): Matsuo Hirotaka、Noguchi Yoshihiko、Miyano Rei、Higo Mayuka、Nonaka Kenichi、Sunazuka Toshiaki、Takahashi Yoko、Omura Satoshi、Nakashima Takuji
  • Journal Title: Antibiotics Volume: 9 Issue: 5 Pages: 236-236
  • DOI: 10.3390/antibiotics9050236
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Nonantibiotic Macrolide EM900 Attenuates House Dust Mite-Induced Airway Inflammation in a Mouse Model of Obesity-Associated Asthma (2020)
  • Author(s): Sadamatsu Hironori、Takahashi Koichiro、Tashiro Hiroki、Kurihara Yuki、Kato Go、Uchida Masaru、Noguchi Yoshihiko、Kurata Keigo、Omura Satoshi、Sunazuka Toshiaki、Kimura Shinya、Sueoka-Aragane Naoko
  • Journal Title: International Archives of Allergy and Immunology Volume: 181 Issue: 9 Pages: 665-674
  • DOI: 10.1159/000508709
  • Peer Reviewed
• [Journal Article] Nanaomycin K, a new epithelial?mesenchymal transition inhibitor produced by the actinomycete “Streptomyces rosa subsp. notoensis” OS-3966 (2020)
  • Author(s): Matsuo Hirotaka、Nakanishi Jun、Noguchi Yoshihiko、Kitagawa Koichi、Shigemura Katsumi、Sunazuka Toshiaki、Takahashi Yoko、Omura Satoshi、Nakashima Takuji
  • Journal Title: Journal of Bioscience and Bioengineering Volume: 129 Issue: 3 Pages: 291-295
  • DOI: 10.1016/j.jbiosc.2019.09.007
  • NAID: 40022194469
  • Peer Reviewed
• [Journal Article] Trichothioneic acid, a new antioxidant compound produced by the fungal strain Trichoderma virens FKI-7573 (2020)
  • Author(s): Miyano Rei、Matsuo Hirotaka、Mokudai Takayuki、Noguchi Yoshihiko、Higo Mayuka、Nonaka Kenichi、Niwano Yoshimi、Sunazuka Toshiaki、Shiomi Kazuro、Takahashi Yoko、Omura Satoshi、Nakashima Takuji
  • Journal Title: Journal of Bioscience and Bioengineering Volume: 129 Issue: 4 Pages: 508-513
  • DOI: 10.1016/j.jbiosc.2019.11.007
  • NAID: 40022216167
  • Peer Reviewed
• [Journal Article] Efficient synthesis of a ryanodine binding inhibitor verticilide using two practical approache (2020)
  • Author(s): Watanabe, A., Noguchi, Y., Hirose, T., Monma, S., Satake T., Arai, M., Masuda, K., Murashima, N., Shiomi, R., Omura, S., and Sunazuka, T.
  • Journal Title: Tetrahedron Lett. Volume: 61 Issue: 13 Pages: 151699-151703
  • DOI: 10.1016/j.tetlet.2020.151699
  • Peer Reviewed
• [Journal Article] The non-antibiotic macrolide EM900 attenuates HDM and poly(I:C)-induced airway inflammation with inhibition of macrophages in a mouse model (2019)
  • Author(s): Sadamatsu Hironori、Takahashi Koichiro、Tashiro Hiroki、Kato Go、Noguchi Yoshihiko、Kurata Keigo、Omura Satoshi、Kimura Shinya、Sunazuka Toshiaki、Sueoka-Aragane Naoko
  • Journal Title: Inflammation Research Volume: 69 Issue: 1 Pages: 139-151
  • DOI: 10.1007/s00011-019-01302-3
  • Peer Reviewed / Open Access
• [Journal Article] Azithromycin, a 15-membered macrolide antibiotic, inhibits influenza A(H1N1)pdm09 virus infection by interfering with the virus internalization process (2019)
  • Author(s): Tran Huu Dat, Ryuichi Sugamata, Tomoyasu Hirose, Shoichi Suzuki, Yoshihiko Noguchi, Akihiro Sugawara, Fuyu Ito, Tomoko Yamamoto, Shoji Kawachi, Kiyoko S. Akagawa, Satoshi Omura, Toshiaki Sunazuka, Naoki Ito, Masakazu Mimaki, Kazuo Suzuki
  • Journal Title: J. Antibiot. Volume: 72 Issue: 10 Pages: 759-768
  • DOI: 10.1038/s41429-019-0204-x
  • Peer Reviewed / Open Access
• [Journal Article] Jietacins, azoxy natural products, as novel NF-kB inhibitors: discovery, synthesis, biological activity, and mode of action (2019)
  • Author(s): Mariko Watanabe, Akihiro Sugawara, Yoshihiko Noguchi, Tomoyasu Hirose, Satoshi Omura, Toshiaki Sunazuka, Ryouichi Horie
  • Journal Title: Eur. J. Med. Chem. Volume: 178 Pages: 636-647
  • DOI: 10.1016/j.ejmech.2019.05.079
  • Peer Reviewed
• [Journal Article] Erythromycin acts through the ghrelin receptor to attenuate inflammatory responses in chondrocytes and maintain joint integrity (2019)
  • Author(s): Uchimura Tomoya、Nakamura Daisy S.、Link Eric M.、Noguchi Yoshihiko、Omura Satoshi、Sunazuka Toshiaki、Greenblatt David J.、Zeng Li
  • Journal Title: Biochemical Pharmacology Volume: 165 Pages: 79-90
  • DOI: 10.1016/j.bcp.2019.03.014
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Nanaomycin I and J: New nanaomycins generated by mycothiol-mediated compounds from “Streptomyces rosa subsp. notoensis” OS-3966 (2019)
  • Author(s): Matsuo Hirotaka、Noguchi Yoshihiko、Take Akira、Nakanishi Jun、Shigemura Katsumi、Sunazuka Toshiaki、Takahashi Yoko、Omura Satoshi、Nakashima Takuji
  • Journal Title: Journal of Bioscience and Bioengineering Volume: 127 Issue: 5 Pages: 549-553
  • DOI: 10.1016/j.jbiosc.2018.10.013
  • NAID: 40021891586
  • Peer Reviewed
• [Presentation] 環状デプシペプチド類の効率的合成を志向した疎水性タグのワンポット化 (2021)
  • Author(s): 関川 章悟、野口 吉彦、廣瀬 友靖、砂塚 敏明
  • Organizer: 日本薬学会 第141年会
• [Presentation] 抗トリパノソーマ活性を有するActinoallolide Aの全合成研究 (2021)
  • Author(s): 大野 孝典、野口 吉彦、渡邊 彰人、岩月 正人、稲橋 佑起、廣瀬 友靖、砂塚 敏明
  • Organizer: 日本薬学会 第141年会
• [Presentation] Ⅲ型分泌装置(T3SS)阻害活性を有するAurodoxの全合成研究 (2021)
  • Author(s): 大原 基義、池田 朱里、中嶋 明日香、大野 孝典、野口 吉彦、渡邊 彰人、廣瀬 友靖、砂塚 敏明
  • Organizer: 日本薬学会 第141年会
• [Presentation] 抗マラリア活性を有するDiatretolの不斉全合成と構造活性相関研究 (2021)
  • Author(s): 高橋 脩、君嶋 葵、山田 健、菅原 章公、白畑 辰弥、野口 吉彦、岩月 正人、穗苅 玲、石山 亜紀、小林 義典、廣瀬 友靖、砂塚 敏明
  • Organizer: 日本薬学会 第141年会
• [Presentation] 抗嫌気性菌活性を有するエフロトマイシンの全合成研究 (2020)
  • Author(s): 大原 基義、池田 朱里、中嶋 明日香、野口 吉彦、渡邊 彰人、廣瀬 友靖、大村 智、砂塚 敏明
  • Organizer: 日本薬学会 第140年会
• [Presentation] 渡邊 彰人、野口 吉彦、大西 倫、廣瀬 友靖、岩月 正人、大村 智、砂塚 敏明 (2020)
  • Author(s): 抗トリパノソーマ活性を有するアクチノアロライドAの全合成研究 -12員環ラクトンの骨格構築-
  • Organizer: 日本薬学会 第140年会
• [Presentation] 抗嫌気性菌活性を有するエフロトマイシンの全合成研究 (2019)
  • Author(s): 大原 基義、池田 朱里、中嶋 明日香、野口 吉彦、渡邊 彰人、廣瀬 友靖、大村 智、砂塚 敏明
  • Organizer: 第63回日本薬学会 関東支部大会
• [Presentation] 大西 倫、渡邊 彰人、野口 吉彦、廣瀬 友靖、岩月 正人、大村 智、砂塚 敏明 (2019)
  • Author(s): 抗トリパノソーマ活性を有するActinoallolide Aの全合成研究
  • Organizer: 第63回日本薬学会 関東支部大会
• [Remarks] 北里大学大村智記念研究所•大学院感染制御科学府 生物有機化学研究室
  • URL: http://seibutuyuuki.sakura.ne.jp
• [Patent(Industrial Property Rights)] Alkyl-substituted compound having β-lactamase inhibitory activity, and use thereof. (2020)
  • Inventor(s): Koike, Sachiko Ikuma et al
  • Industrial Property Rights Holder: Koike, Sachiko Ikuma et al
  • Industrial Property Rights Type: 特許
  • Filing Date: 2020
  • Acquisition Date: 2020
  • Overseas
• [Patent(Industrial Property Rights)] Prophylactic and/or therapeutic agent for influenza virus infection or corona virus infection containing macrolide compound. (2020)
  • Inventor(s): Suzuki, Kazuo Sugamata et al
  • Industrial Property Rights Holder: Suzuki, Kazuo Sugamata et al
  • Industrial Property Rights Type: 特許
  • Filing Date: 2020
  • Acquisition Date: 2020
  • Overseas
• [Patent(Industrial Property Rights)] Preparation of 2-hydroxy-3,4-dihydro-2H-1,2-benzoxaborinine-8-carboxylic acid derivatives as β-lactamase inhibitors (2019)
  • Inventor(s): Kanai, Toshio
  • Industrial Property Rights Holder: Kanai, Toshio
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
  • Acquisition Date: 2019
  • Overseas
• [Patent(Industrial Property Rights)] Improved method for the synthesis of cyclic depsipeptides, including emodepside and PF1022A (2019)
  • Inventor(s): Heimbach, Dirk; Omura, Satoshi
  • Industrial Property Rights Holder: Heimbach, Dirk; Omura, Satoshi
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
  • Acquisition Date: 2019
  • Overseas
• [Patent(Industrial Property Rights)] Preparation of diazene N-oxide derivatives as novel NF-κB inhibitors (2019)
  • Inventor(s): Omura, Satoshi
  • Industrial Property Rights Holder: Omura, Satoshi
  • Industrial Property Rights Type: 特許
  • Filing Date: 2019
  • Acquisition Date: 2019
  • Overseas