Toward the total synthesis of a hybrid natural product that consists a highly functionalized 11-oxatricycloundecane/macrolide and its structure activity relationships

• Project/Area Number: 24790022
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Chemical pharmacy
• Research Institution: Kitasato University
• Principal Investigator: SUGAWARA Akihiro 北里大学, その他の研究科, 助教 (50581683)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2013: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2012: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: ルミナミシン / 抗嫌気性菌活性 / 全合成 / 11-オキサトリシクロウンデカン / 酸素架橋シスデカリン / マクロライド / 構造活性相関 / 高歪み10員環ラクトン / クロストリジウム属 / シスデカリン / 抗感染症薬

Research Abstract

Luminamicin (1) was found to exhibit selective antibacterial activity against anaerobic bacteria in 1985. It contains a highly functionalized 11-oxatricycloundecane, associated with a 10-membered lactone moiety which possesses a (E)-trisubstituted olefin and a 14-membered macrolactone, with an enol ether conjugated with a maleic anhydride functionality.
We have been focusing on its total synthesis due to its intriguing structure and interesting biological activity. We synthesized a framework of the key intermediate from the unsaturated aldehyde via intramolecular 1,6-oxa-Michael reaction and stereoselective protonation at C4 position. Study toward the total synthesis of 1 is in progress in our laboratory.

Research Products

• [Journal Article] Crystal structures of HIV-1 gp120 envelope glycoprotein in complex with NBD analogues that target the CD4-binding site (2014)
  • Author(s): Young Do Kwon, Judith M. LaLonde, Yongping Yang, Mark A. Elban, Akihiro Sugawara, Joel R. Courter, David M. Jones, Amos B. Smith III, Asim K. Debnath, Peter D. Kwong
  • Journal Title: PLoS One Volume: 9 Issue: 1 Pages: e85940-e85940
  • DOI: 10.1371/journal.pone.0085940
  • 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, Kazuo Suzuki
  • Journal Title: J Antibiot Volume: 67 Issue: 3 Pages: 213-222
  • DOI: 10.1038/ja.2013.132
  • 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): Hirose T, Maita N, Taniguchi H, Sharpless KB, Omura S, Sunazuka T
  • Journal Title: Proc.Natl.Acad.Sci. USA. Volume: 110 Issue: 40 Pages: 15892-15897
  • DOI: 10.1073/pnas.1315049110
  • 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, Toshiaki Sunazuka
  • Journal Title: J Am Chem Soc Volume: 135 Issue: 34 Pages: 12568-12571
  • DOI: 10.1021/ja406657v
  • 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: Bioorg Med Chem Volume: 21 Issue: 11 Pages: 3214-3220
  • DOI: 10.1016/j.bmc.2013.03.047
  • 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 Omura, Toshiaki Sunazuka
  • Journal Title: Bioorg Med Chem Lett Volume: 23 Issue: 8 Pages: 2302-2305
  • DOI: 10.1016/j.bmcl.2013.02.075
  • 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?mura and Toshiaki Sunazuka
  • Journal Title: J. Antibiot. Volume: 65 Issue: 9 Pages: 487-490
  • DOI: 10.1038/ja.2012.51
  • NAID: 10031044227
  • Peer Reviewed
• [Journal Article] Toward the total synthesis of Luminamicin : construction of 14-membered lactone 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, Rokuro Masuma, Satoshi?mura, Toshiaki Sunazuka
  • Journal Title: Tetrahedron Lett. Volume: 53 Issue: 23 Pages: 2813-2816
  • DOI: 10.1016/j.tetlet.2012.03.098
  • Peer Reviewed
• [Presentation] Toward the total synthesis of Luminamicin; construction of 14-membered macrolide with enol ether conjugated with a maleic anhydride (2013)
  • Author(s): Hirokazu Takada, Akihiro Sugawara, Tomoyasu Hirose, Aoi Kimishima, Takanori Matsumaru, Masaki Toda, Takeshi Yamada, Satoshi?mura and Toshiaki Sunazuka
  • Organizer: ICCA-13
  • Place of Presentation: 山梨県(富士ビューホテル)
• [Presentation] Toward the total synthesis of Luminamicin; construction of 11?oxatricyclo[5.3.1. ^1,70^3,8]undecane skeleton (2013)
  • Author(s): Aoi Kimishima, Akihiro Sugawara, Tomoyasu Hirose, Hirokazu Takada, Takanori Matsumaru, Satoshi?mura and Toshiaki Sunazuka
  • Organizer: ICCA-13
  • Place of Presentation: 山梨県(富士ビューホテル)
• [Presentation] Toward the total synthesis of Luminamicin, a specific anti-anaerobic bacteriacide (2013)
  • Author(s): Akihiro Sugawara, Aoi Kimishima, Hirokazu Takada, Tomoyasu Hirose, Takanori Matsumaru, Satoshi?mura, Toshiaki Sunazuka
  • Organizer: Annual Meeting of the American Society of Pharmacognosy
  • Place of Presentation: USA (St. Louis)
• [Presentation] Toward The Total Synthesis Of Luminamicin, A Specific Anti-Anaerobic Bacteriacide (2013)
  • Author(s): Akihiro Sugawara, Aoi Kimishima, Hirokazu Takada, Tomoyasu Hirose, Takanori Matsumaru, Satoshi Omura, Toshiaki Sunazuka
  • Organizer: Annual Meeting of the American Society of Pharmacognosy
  • Place of Presentation: USA (St. Louis)
• [Presentation] Toward the total synthesis of Luminamicin; construction of 14-membered macrolide with enol ether conjugated with a maleic anhydride (2013)
  • Author(s): Hirokazu Takada, Akihiro Sugawara, Tomoyasu Hirose, Aoi Kimishima, Takanori Matsumaru, Masaki Toda, Takeshi Yamada, Satoshi Omura and Toshiaki Sunazuka
  • Organizer: ICCA-13
  • Place of Presentation: Japan (Yamanashi)
• [Presentation] Toward the total synthesis of Luminamicin; construction of 11–oxatricyclo[5.3.1. 1,703,8]undecane skeleton (2013)
  • Author(s): Aoi Kimishima, Akihiro Sugawara, Tomoyasu Hirose, Hirokazu Takada, Takanori Matsumaru, Satoshi Omura and Toshiaki Sunazuka
  • Organizer: ICCA-13
  • Place of Presentation: Japan (Yamanashi)
• [Presentation] Luminamicinの全合成研究 (1)；共役無水マレイン酸含有14員環マクロライドの合成法の確立 (2013)
  • Author(s): 高田拓和、菅原章公、廣瀬友靖、君嶋葵、松丸尊紀、戸田正輝、大村智、砂塚敏明
  • Organizer: 日本薬学会第１３３年会
  • Place of Presentation: 横浜
• [Presentation] Luminamicinの全合成研究(2)；11-oxatricyclo[5.3.1.0]undecane骨格の構築 (2013)
  • Author(s): 君嶋葵、菅原章公、廣瀬友靖、高田拓和、松丸尊紀、戸田正輝、大村智、砂塚敏明
  • Organizer: 日本薬学会第１３３年会
  • Place of Presentation: 横浜
• [Presentation] マクロライド骨格をテンプレートとした新規キチナーゼ阻害剤の創製 (2013)
  • Author(s): 菅原章公、真板宣夫、廣瀬友靖、木村紗穂莉、斉藤佳史、山本剛、渡邉剛志、塩見和朗、中野洋文、谷口寿章、大村智、砂塚敏明
  • Organizer: 日本薬学会第１３３年会
  • Place of Presentation: 横浜
• [Remarks]
  • URL: http://seibutuyuuki.sakura.ne.jp/
• [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
• [Remarks] 北里大学北里生命科学研究所 生物有機化学研究室のホームページ
  • URL: http://seibutuyuuki.sakura.ne.jp