Total Synthesis of Naphthacemycins, Possession of Antibacterial Activity against Methicillin-Resistant Staphylococcus aureus (MRSA)

• Project/Area Number: 24590019
• 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): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2012: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: MRSA / Naphtacemycin / 全合成 / デッツ反応

Outline of Final Research Achievements

The MRSA is typical drug-resistance bacterium, which has recently become a one of the social problem as infecting organism of nosocomial infection. Now, there are some of anti-MRSA drugs, but development of new anti-MRSA drugs is still required due to emergence new drug resistance bacterium. As a result of searching for the new anti-MRSA drug at the Kitasato Institute, novel naphthacemycins have been isolated from the culture broth of streptomyces sp. Bioactivity of these compounds is potentiate activity of imipenem against MRSA, and some of naphthacemycins possess antibacterial activity. Especially naphthacemycin A8 and A9 have potent antibacterial activity against MRSA. The structural feature of naphthacemycins consist of tetracene structure, E ring connected to D ring.
We launched synthetic study of naphthacemycin A9 which has potent antibacterial activity against MRSA. As a result, we have accomplish the first total synthesis of naphthacemycin A9.

Research Products

• [Journal Article] Organocatalytic α-Addition of Isocyanides to Aldehydes (2015)
  • Author(s): Takeshi Yamada, Tomoyasu Hirose, Satoshi Omura and Toshiaki Sunazuka
  • Journal Title: Eur. J. Org. Chem. Volume: 2015 Issue: 2 Pages: 296-301
  • DOI: 10.1002/ejoc.201403313
  • Peer Reviewed
• [Journal Article] An architectonic macrolide library based on a C2-symmetric macrodiolide toward pharmaceutical compositions. (2015)
  • Author(s): Hayato Nakano, Akihiro Sugawara, Tomoyasu Hirose, Hiroaki Gouda, Shuichi Hirono, Satoshi Omura and Toshiaki Sunazuka
  • Journal Title: Tetrahedron Volume: 71 Issue: 37 Pages: 000-000
  • DOI: 10.1016/j.tet.2015.01.030
  • Peer Reviewed
• [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] A concise total synthesis of puberulic acid, potent antimalarial agent (2014)
  • Author(s): Goh Sennari, Tomoyasu Hirose, Masato Iwatsuki, Satoshi Omura, Toshiaki Sunazuka
  • Journal Title: Chem. Comm. Volume: 50 Issue: 63 Pages: 8715-8718
  • DOI: 10.1039/c4cc03134b
  • Peer Reviewed
• [Journal Article] Leucomycin A3, a 16-membered macrolide antibiotic, inhibits Influenza A virus infection and disease progression (2014)
  • Author(s): Ryuichi Sugamata, Akihiro Sugawara, Tomokazu Nagao, Koya Suzuki, Tomoyasu Hirose, Ki-ichi Yamamoto, Masamichi Oshima, Kazuo Kobayashi, Toshiaki Sunazuka, Kiyoko S. Akagawa, Satoshi Omura, Toshinori Nakayama, and Kazuo Suzuki
  • Journal Title: Journal of Antibiotics Volume: 67 Pages: 213-222
  • Peer Reviewed
• [Journal Article] Human acidic mammalian chitinase as a novel target for anti-asthma drug design using in silico screening (2013)
  • Author(s): Masaki Wakasugi, Hiroaki Gouda, Tomoyasu Hirose, Akihiro Sugawara, Tsuyoshi Yamamoto, Kazuro Shiomi, Toshiaki Sunazuka, Satoshi Omura, Shuichi Hirono
  • Journal Title: Bioorganic & Medicinal Chemistry Volume: 21 Pages: 3214-3220
  • Peer Reviewed
• [Journal Article] Structure determination and total synthesis of (+)-16-hydroxy-16,22-dihydroapparicine (2013)
  • Author(s): Tomoyasu Hirose, Yoshihiko Noguchi, Yujiro Furuya, Aki Ishiyama, Masato Iwatsuki, Kazuhiko Otoguro, Satoshi Omura and Toshiaki Sunazuka
  • Journal Title: Chemistry - A European Journal Volume: 19 Pages: 10741-10750
  • Peer Reviewed
• [Journal Article] Asymmetric Total Synthesis of Neoxaline (2013)
  • Author(s): Tetsuya Ideguchi, Takeshi Yamada, Tatsuya Shirahata, Tomoyasu Hirose, Akihiro Sugawara, Yoshinori Kobayashi, Satoshi Omura, and Toshiaki Sunazuka
  • Journal Title: Journal of American Chemical Society Volume: 135 Pages: 12568-12571
  • Peer Reviewed
• [Journal Article] Observation of the controlled assembly of preclick components in the In situ Click Chemistry generation of a chitinase inhibitor (2013)
  • Author(s): Tomoyasu Hirose, Nobuo Maita, Hiroaki Gouda, Jun Koseki, Tsuyoshi Yamamoto, Akihiro Sugawara, Hirofumi Nakano, Kazuro Shiomi, Takeshi Watanabe, Hisaaki Taniguchi, K. Barry Sharpless, Satoshi Omura and Toshiaki Sunazuka
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 110 Pages: 15892-15897
  • Peer Reviewed
• [Journal Article] Borrelidin analogues with antimalarial activity; design, synthesis and biological evaluation against Plasmodium falciparum parasites (2013)
  • Author(s): Akihiro Sugawara, Toshiaki Tanaka, Tomoyasu Hirose, Aki Ishiyama, Masato Iwatsuki, Yoko Takahashi, Kazuhiko Otoguro, Satoshi Ōmura, Toshiaki Sunazuka
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 23 Pages: 2302-2305
  • Peer Reviewed
• [Journal Article] Antimalarial C-9 oxime derivatives from tylosin, produced by click chemistry (2013)
  • Author(s): Ayumi Tsutsui, Tomoyasu Hirose, Aki Ishiyama, Masato Iwatsuki, Arisa Yokota, Hitomi Maruyama, Hidehito Matsui, Kazuhiko Otoguro, Hideaki Hanaki, Satoshi Ōmura and Toshiaki Sunazuka
  • Journal Title: Journal of Antibiotics Volume: 66 Pages: 191-194
  • Peer Reviewed
• [Journal Article] Wickerols A and B: Novel anti-influenza virus diterpenes produced by Trichoderma atroviride FKI-3849 (2012)
  • Author(s): Tsuyoshi Yamamoto, Naoyuki Izumi, Hideaki Ui, Akito Sueki, Rokuro Masuma, Kenichi Nonaka, Tomoyasu Hirose, Toshiaki Sunazuka, Takayuki Nagai
  • Journal Title: Tetrahedron Volume: 68 Pages: 9267-9271
  • Peer Reviewed
• [Journal Article] Novel 12-membered non-antibiotic macrolides, EM900 series with anti-inflammatory and/or immunomodulatory activity; Synthesis, structure activity-relationships and in vivo study (2012)
  • Author(s): Akihiro Sugawara, Akito Sueki, Tomoyasu Hirose, Hideaki Shima, Kiyoko S Akagawa, Satoshi Ōmura and Toshiaki Sunazuka
  • Journal Title: Journal of Antibiotics Volume: 65 Pages: 487-490
  • NAID: 10031044227
  • Peer Reviewed
• [Journal Article] A novel N-glucoside, Makomotindoline, from Makomotake, Zizania latifolia Infected with Ustilago esculenta (2012)
  • Author(s): Tomohiro Suzuki, Jae-Hoon Choi, Takumi Kawaguchi, Kimiko Yamashita, Akio Morita, Hirofumi Hirai, Tomoyasu Hirose, Kaoru Nagai, Satoshi Omura, Toshiaki Sunazuka, Hirokazu Kawagishi
  • Journal Title: Bioorg. Med. Chem. Lett. Volume: 22 Pages: 4246-4248
  • Peer Reviewed
• [Journal Article] Toward the total synthesis of luminamicin: construction of 14-membered lacton framework possessing versatile enol ether moiety (2012)
  • Author(s): Aoi Kimishima, Tomoyasu Hirose, Akihiro Sugawara, Takanori Matsumaru, Kaoru Nakamura, Ken Katsuyama, Masaki Toda, Hirokazu Takada, Rokurou Masuma, Satoshi Ōmura, Toshiaki Sunazuka
  • Journal Title: Tetrahedron Letters Volume: 53 Pages: 2813-2816
  • Peer Reviewed
• [Presentation] 創薬展開を志向したBottromycin A2の構造活性相関研究 (2015)
  • Author(s): 八木田美有、小林豊、山田健、堀松優樹、廣瀬友靖、花木秀明、大村智、砂塚敏明
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 兵庫県神戸市、神戸学院大学
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] 抗嫌気性菌活性を有するLuminamicinの合成研究 (2015)
  • Author(s): 君嶋葵、諸留圭介、高田拓和、松丸尊紀、菅原章公、廣瀬友靖、大村智、砂塚敏明
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 兵庫県神戸市、神戸学院大学
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] インドリンスピロアミナール骨格を有するNeoxaline類の効率的な全合成 (2015)
  • Author(s): 井手口哲也、山田健、白畑辰弥、廣瀬友靖、菅原章公、小林義典、大村智、砂塚敏明
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: 兵庫県神戸市、神戸学院大学
  • Year and Date: 2015-03-25 – 2015-03-28
• [Presentation] クリックケミストリーにより広がる天然有機化合物の活用 (2014)
  • Author(s): 廣瀬友靖
  • Organizer: 創薬資源微生物学、寄附講座開設記念シンポジウム
  • Place of Presentation: 東京都、北里大学 白金キャンパス
  • Year and Date: 2014-11-08
  • Invited
• [Presentation] 構造活性相関研究を志向したBottromycin A2類の合成 (2014)
  • Author(s): 八木田美有、山田 健、堀松優樹、小林 豊、千成 恒、廣瀬友靖、大村 智、砂塚敏明
  • Organizer: 第58回日本薬学会関東支部大会
  • Place of Presentation: 東京都町田市、昭和薬科大学
  • Year and Date: 2014-10-04
• [Presentation] In situクリックケミストリーを利用した高活性キチナーゼ阻害剤の探索研究 (2014)
  • Author(s): 廣瀬友靖
  • Organizer: 平成26年度大会（第63回）応用糖質科学シンポジウム
  • Place of Presentation: 新潟市、朱鷺メッセ新潟コンベンションホール
  • Year and Date: 2014-09-24 – 2014-09-26
  • 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 (2014)
  • Author(s): 山田健、廣瀬友靖、大村智、砂塚敏明
  • Organizer: 有機分子触媒による未来型分子変換、第4回公開シンポジウム
  • Place of Presentation: 北海道札幌市、北海道大学
  • Year and Date: 2014-06-20 – 2014-06-21
• [Presentation] 標的酵素誘導型トリアゾール化を利用した天然物創薬研究 (2014)
  • Author(s): 廣瀬友靖
  • Organizer: 第15回酵素応用シンポジウム
  • Place of Presentation: 名古屋市、天野エンザイム（株）慈善ホール
  • Year and Date: 2014-06-13
  • Invited
• [Presentation] インドリンスピロアミナール骨格を有するNeoxaline類の全合成 (2014)
  • Author(s): 井手口哲也、山田健、白畑辰弥、廣瀬友靖、菅原章公、小林義典、大村智、砂塚敏明
  • Organizer: 第105回有機合成シンポジウム
  • Place of Presentation: 東京都、東京工業大学、大岡山キャンパス
  • Year and Date: 2014-06-10 – 2014-06-11
• [Presentation] 抗マラリア活性を有するPuberulic acid類の多様性指向型合成 (2014)
  • Author(s): 千成恒、廣瀬友靖、岩月正人、石山亜紀、乙黒一彦、大村智、砂塚 敏明
  • Organizer: 日本薬学会第134年会
  • Place of Presentation: 熊本県（熊本大学）
• [Presentation] インドリンスピロアミナール骨格を有するNeoxalineの全合成 (2013)
  • Author(s): 井手口哲也、山田健、白畑辰弥、廣瀬友靖、菅原章公、小林義典、大村智、砂塚敏明
  • Organizer: 第11回次世代を担う有機合成シンポジウム
  • Place of Presentation: 東京都（日本薬学会長井記念ホール）
• [Presentation] Asymmetric Total Synthesis of Neoxaline (2013)
  • Author(s): Tetsuya Ideguchi, Takeshi Yamada, Tatsuya Shirahata, Tomoyasu Hirose, Akihiro Sugawara, Yoshinori Kobayashi, Satoshi Omura and Toshiaki Sunazuka
  • Organizer: ICCA-13
  • Place of Presentation: 山梨県（富士ビューホテル）
• [Presentation] Total synthesis of Puberulic Acid, a potent antimalarial (2013)
  • Author(s): Goh Sennari, Tomoyasu Hirose, Masato Iwatsuki, Aki Ishiyama, Kazuhiko Otoguro, Satoshi Omura, and Toshiaki Sunazuka
  • Organizer: ICCA-13
  • Place of Presentation: 山梨県（富士ビューホテル）
• [Presentation] 天然物を基盤としたin situ click chemistry (2013)
  • Author(s): 廣瀬友靖
  • Organizer: 有機合成化学ミニシンポジウム
  • Place of Presentation: 東京都（北里大学白金キャンパス)
  • Invited
• [Book] クリックケミストリー –基礎から実用まで- (2014)
  • Author(s): 廣瀬友靖、砂塚敏明
  • Total Pages: 10
  • Publisher: シーエムシー出版
• [Book] 月刊ファインケミカル2月号 (2014)
  • Author(s): 廣瀬友靖、砂塚敏明
  • Total Pages: 8
  • Publisher: シーエムシー出版