Toward the total synthesis of novel anti-protozoal 12-membered macrolides

• Project/Area Number: 15K07866
• 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: Hirose Tomoyasu 北里大学, 感染制御科学府, 准教授 (00370156)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 全合成 / アクチノアロライド / マクロライド / トリパノソーマ / 新規天然物 / actinoallolide

Outline of Final Research Achievements

Trypanosomiasis is caused by the parasitic flagellated protozoa. During the course of physicochemical screening for metabolites, new anti-trypanosomal macrolides, actinoallolides, were discovered. Among them, actinoallolide A showed most potent and selective anti-trypanosomal activity. Due to its intriguing architectural structure and interesting biological activity, we thus became interested to determination of their absolute and total synthesis of actinoallorides.
We first determined the absolute configuration of actinoalloride A by single-crystal X-ray crystallographic analysis of its acylation derivative. We next commenced to pursue the synthetic studies of actinoalloride A to provide clarification of detailed structure-activity relationships. So far, we have achieved the synthesis of an essential intermediate including full carbon framework in the total synthesis of Actinoallolide A.

Research Products

• [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] Nanaomycin H: A new nanaomycin analog (2017)
  • Author(s): Takuji Nakashima, Toru Kimura, Rei Miyano, Hirotaka Matsuo, Tomoyasu Hirose, Aoi Kimishima, Kenichi Nonaka, Masato Iwatsuki, Jun Nakanishi, Yoko Takahashi and Satoshi Omura
  • Journal Title: Journal of Bioscience Bioengineering Volume: 123 Issue: 6 Pages: 765-770
  • DOI: 10.1016/j.jbiosc.2017.01.011
  • NAID: 40021226035
  • Peer Reviewed
• [Journal Article] 5-O-Mycaminosyltylonolide antibacterial derivatives: Design, synthesis and bioactivity (2017)
  • Author(s): Akihiro Sugawara, Hitomi Maruyama, Sho Shibusawa, Hidehito Matsui, Tomoyasu Hirose, Ayumi Tsutsui, Robrecht Froyman, Carolin Ludwig, Johannes Koebberling, Hideaki Hanaki, Gerd Kleefeld, Satoshi Omura, Toshiaki Sunazuka
  • Journal Title: J. Antibiot. Volume: 70 Issue: 8 Pages: 878-887
  • DOI: 10.1038/ja.2017.61
  • Peer Reviewed
• [Journal Article] Antimalarial troponoids, puberulic acid and viticolins; divergent synthesis and biological evaluation (2017)
  • Author(s): Goh Sennari, Ryo Saito, Tomoyasu Hirose, Masato Iwatsuki, Aki Ishiyama, Rei Hokari, Kazuhiko Otoguro, Satoshi Omura, and Toshiaki Sunazuka
  • Journal Title: Scientific Report Volume: - Issue: 1
  • DOI: 10.1038/s41598-017-07718-3
  • Peer Reviewed / Open Access
• [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] 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] 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] <i>In Situ</i> Click Chemistry for the Identification of a Potent D-Amino Acid Oxidase Inhibitor (2016)
  • Author(s): Toguchi Shohei, Hirose Tomoyasu, Yorita Kazuko, Fukui Kiyoshi, Sharpless K. Barry, Omura Satoshi, Sunazuka Toshiaki
  • Journal Title: Chemical and Pharmaceutical Bulletin Volume: 64 Issue: 7 Pages: 695-703
  • DOI: 10.1248/cpb.c15-00867
  • NAID: 130005160055
  • ISSN: 0009-2363, 1347-5223
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Organocatalytic Site-Selective Acylation of Avermectin B_2a, 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: Chemical and Pharmaceutical Bulletin Volume: 64 Issue: 7 Pages: 856-864
  • DOI: 10.1248/cpb.c16-00205
  • NAID: 130005160046
  • ISSN: 0009-2363, 1347-5223
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Synthesis and stereochemical determination of an antiparasitic pseudo-aminal type monoterpene indole alkaloid. (2016)
  • Author(s): Noguchi Yoshihiko, Hirose Tomoyasu, Ishiyama Aki, Iwatsuki Masato, Otoguro Kazuhiko, Sunazuka Toshiaki, Omura Satoshi
  • Journal Title: J. Nat. Med. Volume: 70 Issue: 3 Pages: 302-317
  • DOI: 10.1007/s11418-016-1012-2
  • Peer Reviewed
• [Journal Article] Rapid Identification via In Situ Click Chemistry of a Novel Chitinase Inhibitor (2016)
  • Author(s): Hirose Tomoyasu, Sunazuka Toshiaki, Omura Satoshi
  • Journal Title: Journal of Synthetic Organic Chemistry Volume: 74 Pages: 1090-1097
  • NAID: 130005433321
  • Peer Reviewed
• [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
• [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] Jietacins with potent nematocidal activity; efficient isolation of novel analogues and divergent total synthesis of jietacin A, B, C, and D (2015)
  • Author(s): 4) Akihiro Sugawara, Masahiko Kubo, Takuji Nakashima, Tomoyasu Hirose, Noriaki Tsunoda, Kyoichi Yahagi, Yukihiro Asami, Takeshi Yamada, Kazuro Shiomi, Yoko Takahashi, Satoshi Omura, Toshiaki Sunazuka
  • Journal Title: Tetrahedron Volume: 71 Issue: 14 Pages: 2149-2157
  • DOI: 10.1016/j.tet.2015.02.038
  • Peer Reviewed
• [Journal Article] Asymmetric Total Synthesis of Indole Alkaloids Containing an Indoline Spiroaminal Framework (2015)
  • Author(s): Takeshi Yamada, Tetsuya Ideguchi-Matsushita, Tomoyasu Hirose, Tatsuya Shirahata, Rei Hokari, Aki Ishiyama, Masato Iwatsuki, Akihiro Sugawara, Yoshinori Kobayashi, Kazuhiko Otoguro, Satoshi Omura, Toshiaki Sunazuka
  • Journal Title: Chemistry - A European Journal Volume: 21 Issue: 33 Pages: 11855-11864
  • DOI: 10.1002/chem.201501150
  • Peer Reviewed / Open Access
• [Journal Article] Creation of Customized Bioactivity within a 14-Membered Macrolide Scaffold: Design, Synthesis, and Biological Evaluation Using a Family-18 Chitinase (2015)
  • Author(s): Akihiro Sugawara, Nobuo Maita, Hiroaki Gouda, Tsuyoshi Yamamoto, Tomoyasu Hirose, Saori Kimura, Yoshifumi Saito, Hayato Nakano, Takako Kasai, Hirofumi Nakano, Kazuro Shiomi, Shuichi Hirono, Takeshi Watanabe, Hisaaki Taniguchi, Satoshi Omura, Toshiaki Sunazuka
  • Journal Title: Journal of Medicinal Chemistry Volume: 58 Issue: 12 Pages: 4984-4997
  • DOI: 10.1021/acs.jmedchem.5b00175
  • Peer Reviewed
• [Presentation] 抗トリパノソーマ活性を有するActinoallolide Aの全合成研究 (2018)
  • Author(s): 渡邊 彰人、野口吉彦、廣瀬友靖、佐藤翔悟、千成 恒、岩月正人、稲橋佑起大村 智、砂塚 敏明
  • Organizer: 日本薬学会第138年会
• [Presentation] 抗マラリア活性トロポノイド類の多様性指向型合成と構造活性相関研究 (2018)
  • Author(s): 千成 恒、齋藤亮、廣瀬友靖、岩月正人、石山亜紀、穂刈 玲、乙黒一彦、大村 智、砂塚 敏明
  • Organizer: 日本薬学会第138年会
• [Presentation] 疎水性タグを用いた殺虫活性を示す24員環デプシペプチドVerticilideの全合成 (2018)
  • Author(s): 野口吉彦、廣瀬友靖、佐竹雄大、村島徳史、野垣祐貴、塩見和朗、大村 智、砂塚敏明
  • Organizer: 日本薬学会第138年会
• [Presentation] コンビナトリアルライブラリーの構築を指向したエバーメクチン類の全合成研究 ; ファーマコフォアフラグメントの合成 (2017)
  • Author(s): 千成 恒、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137年会
  • Place of Presentation: 仙台（東北大学）
  • Year and Date: 2017-03-25
• [Presentation] 抗トリパノソーマ活性を有する Actinoallolide A の全合成研究 (2017)
  • Author(s): 渡邊 彰人、野口吉彦、廣瀬友靖、佐藤翔悟、千成 恒、岩月正人、稲橋佑起大村 智、砂塚 敏明
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台（東北大学）
  • Year and Date: 2017-03-25
• [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: 仙台（東北大学）
  • Year and Date: 2017-03-25
• [Presentation] 嫌気性菌活性を有するルミナミシンの全合成研究 ;三置換オレフィンを含むサザンパートの合成 (2017)
  • Author(s): 安藤 博康、菅原章公、廣瀬友靖、大原基義、君嶋 葵、高田拓和、大村 智、砂塚敏明
  • Organizer: 日本薬学会第137年会
  • Place of Presentation: 仙台（東北大学）
  • Year and Date: 2017-03-25
• [Presentation] アゾキシ天然物 Jietacin のバイオイソスターを考慮した類縁体の合成 (2017)
  • Author(s): 菅原章公、久保雅彦、廣瀬友靖、矢作恭一、Claudia WELZ、Cristina MERTENS、Johannes KOBBERLING、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: 仙台（東北大学）
  • Year and Date: 2017-03-25
• [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] 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、穂刈 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] Progress toward the total synthesis of Actinoallolide A, potent anti-trypanosomal macrolide (2017)
  • Author(s): 渡邊彰人、野口吉彦、佐藤翔悟、千成 恒、岩月正人、稲橋佑起、廣瀬友靖、大村 智、砂塚敏明
  • Organizer: 第112回有機合成シンポジウム
• [Presentation] 抗嫌気性菌活性を有するルミナミシンの全合成研究 (2017)
  • Author(s): 安藤博康、大原基義、宮本岳洋、廣瀬友靖、大村 智、砂塚敏明
  • Organizer: 第112回有機合成シンポジウム
• [Presentation] 薬作りへの有機分子触媒の活用 (2016)
  • Author(s): 砂塚敏明、山田 健、廣瀬友靖、大村 智
  • Organizer: 第6回CSJ化学フェスタ2016
  • Place of Presentation: 東京（タワーホール船堀）
  • Year and Date: 2016-11-14
  • Invited
• [Presentation] 有機分子触媒を用いたイソシアニドとアルデヒドのα-付加反応 (2016)
  • Author(s): 山田 健、廣瀬友靖、大村 智、砂塚敏明
  • Organizer: 第110回有機合成シンポジウム2016年【秋】
  • Place of Presentation: 東京（早稲田大学国際会議場）
  • Year and Date: 2016-11-10
• [Presentation] 顧みられない熱帯病、トリパノソーマ症に有効なマングロマイシン類の全合成研究 (2016)
  • 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: 第110回有機合成シンポジウム2016年【秋】
  • Place of Presentation: 東京（早稲田大学国際会議場）
  • Year and Date: 2016-11-10
• [Presentation] 抗嫌気性菌活性を有するLuminamicinの全合成研究 (2016)
  • Author(s): 安藤博康、君嶋 葵、高田拓和、諸留圭介、松丸尊紀、菅原章公、廣瀬友靖、大村 智、砂塚敏明
  • Organizer: 第109回有機合成シンポジウム
  • Place of Presentation: 東京（東京工業大学大岡山キャンパス）
  • Year and Date: 2016-06-08
• [Presentation] 抗トリパノソーマ活性を有するActinoallolide Aの全合成研究 (2016)
  • Author(s): 渡邊彰人、大下 純、野口吉彦、及川大揮、岩月正人、稲橋佑起、廣瀬友靖、大村 智、砂塚敏明
  • Organizer: 第109回有機合成シンポジウム
  • Place of Presentation: 東京（東京工業大学大岡山キャンパス）
  • Year and Date: 2016-06-08
• [Presentation] Utilization of in situ click chemistry to discover novel chitinase inhibitors (2016)
  • Author(s): Tomoyasu Hirose, Nobuo Maita, Takeshi Watanabe, Hisaaki Taniguchi, K. Barry Sharpless, Satoshi Omura and 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
• [Presentation] 抗トリパノソーマ活性を有する新規マクロライド、Actinoallolide類の全合成研究 (2016)
  • Author(s): 渡邊彰人、大下 純、野口吉彦、及川大輝、廣瀬友靖、稲橋正人、稲橋佑起、大村 智、砂塚敏明
  • Organizer: 日本薬学会第136年会
  • Place of Presentation: パシフィコ横浜、神奈川県横浜市
  • Year and Date: 2016-03-27
• [Presentation] Determination of absolute stereochemistry and toward the total synthesis of actinoallolides, new anti-trypanosomal macrolides, produced by an endophytic actinomycete (2015)
  • Author(s): T. Hirose, J. Oshita, D. Oikawa, Y. Inahashi, M. Iwatsuki, A. Matsumoto, S. Omura and T. Sunazuka
  • Organizer: ICCA-14
  • Place of Presentation: Texas, USA
  • Year and Date: 2015-10-13
  • Int'l Joint Research
• [Presentation] 抗トリパノソーマ活性を有するActinoallolide Aの全合成研究 (2015)
  • Author(s): 渡邊彰人、大下 純、野口吉彦、及川大輝、岩月正人、稲橋佑起、廣瀬友靖、大村 智、砂塚敏明
  • Organizer: AKPS集会第9回北里化学シンポジウム
  • Place of Presentation: 北里大学白金キャンパス、東京都港区
  • Year and Date: 2015-09-26
• [Presentation] 抗トリパノソーマ活性を有するActinoallolide Aの全合成研究 (2015)
  • Author(s): 渡邊彰人、大下 純、野口吉彦、及川大輝、岩月正人、稲橋佑起、廣瀬友靖、大村 智、砂塚敏明
  • Organizer: 第59回 日本薬学会 関東支部大会
  • Place of Presentation: 日本大学薬学部、千葉県船橋市
  • Year and Date: 2015-09-12