Cascade and efficient total synthesisor for drug discovery of tropical disease

• Project/Area Number: 16K08174
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Chemical pharmacy
• Research Institution: Kitasato University
• Principal Investigator: Sunazuka Toshiaki 北里大学, 感染制御科学府, 教授 (30226592)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2018: ¥260,000 (Direct Cost: ¥200,000、Indirect Cost: ¥60,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2016: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 顧みられない熱帯病 / アフリカ睡眠病 / 全合成 / 絶対構造決定 / マクロラクトン化 / 籠状構造 / 向山型ビニロガスアルキル化反応 / 不斉合成 / 得意な環状構造 / カスケード反応 / 向山アルドール反応 / 熱帯病治療薬 / 特異な環状構造 / ケトエノール互変異性 / 絶対立体構造を決定 / 顧みられない病気 / 熱帯病 / 網羅的

Outline of Final Research Achievements

An enantioselective total synthesis of (+)-mangromicin A has been accomplished. The tetrahydrofuran ring of mangromicin A, possessing a tetrasubstituted carbon center, was constructed by Mukaiyama-type vinylogous alkylation via a cyclic oxocarbenium intermediate derived from a γ-hydroxy ketone with ideal stereoselectivity, and the 4-hydroxydihydropyrone scaffold was generated via Dieckmann cyclization at a late stage of the total synthesis. The reliable asymmetric synthesis of (+)-mangromicin A has revealed the absolute configuration of naturally occurring mangromicin A.

Academic Significance and Societal Importance of the Research Achievements

アフリカを含む熱帯地域で問題になっている寄生虫病であるアフリカ睡眠病の新たな治療薬の創製を目的に、我々のグループで微生物代謝物をスクリーニングした結果、新たな天然物としてマングロマイシンが発見された。そこで、マングロマイシンに関して絶対構造の決定と初の全合成に成功した。今後、マングロマイシンが世界で問題になっている熱帯病の治療薬になる事が期待される。

Research Products

• [Journal Article] Kozupeptins, Antimalarial Agents Produced by Paracamarosporium Species: Isolation, Structural Elucidation, Total Synthesis, and Bioactivity (2019)
  • Author(s): Hayashi Yumi、Fukasawa Wataru、Hirose Tomoyasu、Iwatsuki Masato、Hokari Rei、Ishiyama Aki、Kanaida Masahiro、Nonaka Kenichi、Take Akira、Otoguro Kazuhiko、Omura Satoshi、Shiomi Kazuro、Sunazuka Toshiaki
  • Journal Title: Organic Letters Volume: 21 Issue: 7 Pages: 2180-2184
  • DOI: 10.1021/acs.orglett.9b00483
  • Peer Reviewed
• [Journal Article] Insecticidal properties of pyripyropene A, a microbial secondary metabolite, against agricultural pests (2018)
  • Author(s): Ryo Horikoshi, Kimihiko Goto, Masaaki Miomi, Kazuhiko Oyama, Toshiaki Sunazuka, Satoshi Omura.
  • Journal Title: Journal of Pesticide Science Volume: 43 Issue: 4 Pages: 266-271
  • DOI: 10.1584/jpestics.D18-030
  • NAID: 130007520014
  • ISSN: 1348-589X, 1349-0923
  • Year and Date: 2018-11-20
  • Peer Reviewed
• [Journal Article] Pestynol, a novel antifungal compound discovered using a Saccharomyces cerevisiae 12geneΔ0HSR-iERG6-based assay (2018)
  • Author(s): Katsuyuki Sakai, Tomoyasu Hirose, Masato Iwatsuki, Takumi Chinen, Toru Kimura, Takuya Suga, Kenichi Nonaka, Takuji Nakashima, Toshiaki Sunazuka, Takeo Usui, Yukihiro Asami, Satoshi Omura, Kazuro Shiomi
  • Journal Title: J. Nat. Prod. Volume: 81 Issue: 7 Pages: 1604-1609
  • DOI: 10.1021/acs.jnatprod.8b00200
  • Peer Reviewed
• [Journal Article] Synthesis and insecticidal efficacy of pyripyropene derivatives focusing on the C-1, C-7, and C-11 positions' substituent groups (2018)
  • Author(s): Kimihiko Goto, Ryo Horikoshi, Masaaki Mitomi, Kazuhiko Oyama, Tomoyasu Hirose, Toshiaki Sunazuka, Satoshi Omura
  • Journal Title: J. Antibiot. Volume: 72 Issue: 9 Pages: 785-797
  • DOI: 10.1038/s41429-018-0064-9
  • Peer Reviewed
• [Journal Article] Synthesis and evaluation of antibacterial activity of bottromycins (2018)
  • Author(s): Takeshi Yamada, Miu Yagita, Yutaka Kobayashi, Goh Sennari, Hiroyuki Shimamura, Hidehito Matsui, Yuki Horimatsu, Hideaki Hanaki, Tomoyasu Hirose, Satoshi Omura, Toshiaki Sunazuka
  • Journal Title: Journal of Organic Chemistry Volume: 83 Issue: 13 Pages: 7135-7149
  • DOI: 10.1021/acs.joc.8b00045
  • Peer Reviewed
• [Journal Article] Jietacins, azoxy antibiotics with potent nematocidal activity: Design, synthesis, and biological evaluation against parasitic nematodes (2018)
  • Author(s): Sugawara Akihiro、Kubo Masahiko、Hirose Tomoyasu、Yahagi Kyoichi、Tsunoda Noriaki、Noguchi Yoshihiko、Nakashima Takuji、Takahashi Yoko、Welz Claudia、Mueller Dennis、Mertens Christina、Koebberling Johannes、?mura Satoshi、Sunazuka Toshiaki
  • Journal Title: European Journal of Medicinal Chemistry Volume: 145 Pages: 524-538
  • DOI: 10.1016/j.ejmech.2017.12.031
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Toward the total synthesis of luminamicin; an anaerobic antibiotic: construction of highly functionalized cis-decalin containing a bridged ether moiety. (2017)
  • Author(s): Hiroyasu Ando, Aoi Kimishima, Motoyoshi Ohara, Tomoyasu Hirose, Takanori Matsumaru, Hirokazu Takada, Keisuke Morodome, Takehiro Miyamoto, Akihiro Sugawara, Satoshi Omura and Toshiaki Sunazuka
  • Journal Title: J. Antibiot. Volume: 71 Issue: 2 Pages: 268-272
  • DOI: 10.1038/ja.2017.77
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Stereo- and substituent-enabled divergent synthesis of 5,6-spiroketal analogs of avermectin containing a triazole function. (2017)
  • Author(s): Takeshi Yamada, Yuki Horimatsu, Tomoyasu Hirose, Akihiro Sugawara, Satoshi Omura and Toshiaki Sunazuka.
  • Journal Title: Tetrahedron Lett. 58 Volume: 58 Issue: 32 Pages: 3119-3124
  • DOI: 10.1016/j.tetlet.2017.06.072
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Total synthesis of (±)-naphthacemycin A9, possessing both antibacterial activity against methicillin-resistant Staphylococcus aureus and circumventing effect of β-lactam resistance. (2017)
  • Author(s): Tomoyasu Hirose, Yasuhiro Kojima, Hidehito Matsui, Hideaki Hanaki, Masato Iwatsuki, Kazuro Shiomi, Satoshi Omura and Toshiaki Sunazuka
  • Journal Title: J. Antibiot. Volume: 70 Issue: 5 Pages: 574-581
  • DOI: 10.1038/ja.2016.141
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Naphthacemycins, novel circumventors of β-lactam resistance in MRSA, produced by Streptomyces sp. KB-3346-5. II. Structure elucidation. (2017)
  • Author(s): Atsushi Fukumoto, Yong-Pil Kim, Masato Iwatsuki, Tomoyasu Hirose, Toshiaki Sunazuka, Hideaki Hanaki, Satoshi Omura and Kazuro Shiomi.
  • Journal Title: J. Antibiot. Volume: 70 Issue: 5 Pages: 568-573
  • DOI: 10.1038/ja.2017.29
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Total Synthesis and Determination of the Absolute Configuration of Naturally Occurring Mangromicin A, with Potent Antitrypanosomal Activity (2017)
  • Author(s): Hirokazu Takada, Takeshi Yamada, Tomoyasu Hirose, Takuma Ishihara, Takuji Nakashima, Yoko Takahashi, Satoshi Omura, Toshiaki Sunazuka
  • Journal Title: Organic Letters Volume: 19 Issue: 1 Pages: 230-233
  • DOI: 10.1021/acs.orglett.6b03512
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Towards the total synthesis of the anti-trypanosomal macrolide, Actinoallolides: construction of a key linear intermediate (2016)
  • Author(s): Jun Oshita, Yoshihiko Noguchi, Akito Watanabe, Goh Sennari, Shogo Sato, Tomoyasu Hirose, Daiki Oikawa, Yuki Inahashi, Masato Iwatsuki, Aki Ishiyama, Satoshi Omura and Toshiaki Sunazuka
  • Journal Title: Tetrahedron Lett. Volume: 57 Issue: 3 Pages: 357-360
  • DOI: 10.1016/j.tetlet.2015.12.022
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Organocatalytic Site-Selective Acylation of 10-Deacetylbaccatin III (2016)
  • Author(s): Yanagi Masanori, Ryo Ninomiya, Yoshihiro Ueda, Takumi Furuta, Takeshi Yamada, Toshiaki Sunazuka, Takeo Kawabata
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 64 Issue: 7 Pages: 907-912
  • DOI: 10.1248/cpb.c16-00037
  • NAID: 130005160042
  • ISSN: 0009-2363, 1347-5223
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Organocatalytic Site-Selective Acylation of Avermectin B2a, a Unique Endectocidal Drug (2016)
  • Author(s): Takeshi Yamada, Koh Suzuki, Tomoyasu Hirose, Takumi Furuta, Yoshihiro Ueda, Takeo Kawabata, Satoshi Omura and Toshiaki Sunazuka
  • Journal Title: Chem. Pharm. Bull Volume: 64 Pages: 856-864
  • NAID: 130005160046
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] The Design, Synthesis, and Evaluation of 1,5,7-Trisubstituted-3-Pyridyl-Xanthones for Use as Insecticides Starting from Pyripyropene A (2016)
  • Author(s): Shinichiro Fuse, Keisuke Matsumura, Kohei Johmoto, Hidehiro Uekusa, Hiroshi Tanaka, Tomoyasu Hirose, Toshiaki Sunazuka, Satoshi Omura, Takashi Takahashi
  • Journal Title: Chem. Eur. J. Volume: 51 Issue: 51 Pages: 18450-18455
  • DOI: 10.1002/chem.201603980
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] コンビナトリアルライブラリー構築を指向したエバーメクチン類の全合成研究 (2019)
  • Author(s): 齋藤亮、君嶋葵、千成恒、佐藤翔悟、廣瀬友靖、増井悠、高橋孝志、大村智、砂塚敏明
  • Organizer: 日本薬学会 第139回年会
• [Presentation] 疎水性タグを用いた環状デプシペプチド類の全合成 (2019)
  • Author(s): 野口吉彦、野垣祐貴、廣瀬友靖、村島徳史、佐竹雄大、大村智、砂塚敏明
  • Organizer: 日本薬学会 第139回年会
• [Presentation] 大村創薬グループにおける微生物創薬 (2018)
  • Author(s): 砂塚 敏明
  • Organizer: 第36回メディシナルケミストリーシンポジウム
  • Invited
• [Presentation] 日本発の大村天然物による微生物創薬 (2018)
  • Author(s): 砂塚 敏明
  • Organizer: 平成30年度後期有機合成化学講習会
  • Invited
• [Presentation] 薬剤感受性出芽酵母を用いた微生物二次代謝産物からの抗真菌薬シード化合物の探索 (2018)
  • Author(s): 坂井克行，廣瀬友靖，岩月正人、知念拓実、木村徹、須賀拓弥，野中健一、中島琢自、砂塚敏明、臼井健郎，浅見行弘、大村智、塩見和朗
  • Organizer: 第101回 日本細菌学会関東支部総会
• [Presentation] 抗トリパノソーマ活性を有するMangromicin Aの全合成と絶対立体構造の決定 (2017)
  • Author(s): 高田拓和、山田 健、廣瀬友靖、石原拓真、中島琢自、高橋洋子、大村 智、砂塚敏明
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 東北大学、宮城県仙台市
  • Year and Date: 2017-03-25
• [Presentation] 微生物由来天然物をリード化合物とする創薬の方向性 (2017)
  • Author(s): 砂塚敏明
  • Organizer: 第91回日本感染症学会総会学術講演会、第65回日本化学療法学術集会 合同学会
  • Invited
• [Presentation] 大村天然物の可能性を引き出す創薬研究 (2017)
  • Author(s): 砂塚敏明
  • Organizer: 第22回日本病態プロテアーゼ学会学術集会
  • Invited
• [Presentation] 抗トリパノソーマ活性を有するマングロマイシン類の単離、構造決定ならびに不斉全合成 (2017)
  • Author(s): 廣瀬 友靖、中島 琢自、高田 拓和、岩月 正人、山田 健、落合 純也、神谷 義之、石原 拓真、長井 賢一郎、松本 厚子、石山 亜紀、乙黒 一彦、塩見 和朗、高橋 洋子、砂塚 敏明、大村 智
  • Organizer: 第59回天然有機化合物討論会
• [Presentation] 北里微生物資源ライブラリーを基盤とした多剤耐性菌を克服する天然物創薬 (2017)
  • Author(s): 砂塚敏明
  • Organizer: 薬剤耐性(AMR)シンポジウム
  • Invited
• [Presentation] 抗マラリア活性を有するPuberulic acid類の全合成と構造活性相関研究 (2017)
  • Author(s): 齋藤 亮、千成 恒、廣瀬 友靖、岩月 正人、石山 亜紀、穂苅 玲、乙黒 一彦、大村 智、砂塚 敏明
  • Organizer: 第35回メディシナルケミストリーシンポジウム
• [Presentation] 北里発の微生物由来天然物の合成と創薬展開 (2016)
  • Author(s): 砂塚敏明
  • Organizer: 第33回有機合成化学セミナー
  • Place of Presentation: ヒルトンニセコビレッジ、北海道虻田郡
  • Year and Date: 2016-09-06
  • Invited
• [Presentation] Microbial Natural Products as Splendid Gifts for Drug Discovery for Human, Animal and Agriculture (2016)
  • Author(s): Toshiaki Sunazuka
  • Organizer: The 71th Annual Academic Congress of Korean Association of Biological Sciences
  • Place of Presentation: Samyuk University, Korea
  • Year and Date: 2016-08-10
  • Int'l Joint Research / Invited
• [Presentation] Synthetic Strategy for Construction of Unique Polycyclic Natural Products (2016)
  • Author(s): Toshiaki Sunazuka
  • Organizer: Natural Products & Bioactive Compounds Gordon Research Conference
  • Place of Presentation: Proctor Academy Andover, NH, US.
  • Year and Date: 2016-07-31
  • Int'l Joint Research / Invited
• [Presentation] In the Harmony between Natural Products and Organic Synthesis (2016)
  • Author(s): Toshiaki Sunazuka
  • Organizer: 25th French-Japanese Symposium on Medicinal and Fine Chemistry (FJS 2016)
  • Place of Presentation: Keio Plaza Hotel Tama, Japan
  • Year and Date: 2016-05-15
  • Int'l Joint Research / Invited
• [Remarks] 北里大学北里生命科学研究所・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