Study on synthetic sapnonins, candidates of vaccine adjuvant, via construction of glycosidic bond at C28 ester moiety by using microflow reactor.

• Project/Area Number: 24790021
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Chemical pharmacy
• Research Institution: Kitasato University
• Principal Investigator: SHIRAHATA Tatsuya 北里大学, 薬学部, 講師 (30414056)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 配糖化 / ワクチンアジュバント / マイクロフローリアクター / 配当化

Research Abstract

Against various infection diseases such as Influenza, clinical advance in effective and safety usage of vaccine depends on potent adjuvant. Onjisaponins included in Polygala tenuifolia Willd., were identified. Further drug development of these saponins is hampered by poor isolation yields. Even though synthetic attempt, the problem has been remained for the construction of C28 glycosided bond in oleanolic acid and the introduction of cinnamoyl group.Herein we examined C28 glycosylation as a key step for the synthesis of simple saponin, for purpose of showing their adjuvant activity.
In order to construct simple glucose moiety, chemoselective and regioselective construction of various esters was accomplished. A sensitive C28 glycosyl ester linkage was constructed by using micro flow reactor. In addition, a process for the preparation of tenuifolin, a natural triterpene, was achieved.

Research Products

• [Journal Article] Petersson, George A.;?mura, Satoshi; Shiomi, Kazuro : Aogacillins A and B produced by Simplicillium sp. FKI-5985: new circumventor s of ar bekacin resistance in MRSA (2013)
  • Author(s): Takata, Keiko; Iwatsuki, Masato; Yamamoto, Tsuyoshi; Shirahata, Tatsuya; Nonaka, Kenichi; Masuma, Rokuro; Hayakawa, Yoichi; Hanaki, Hideaki; Kobayashi, Yoshinori
  • Journal Title: Organic Letters Volume: 15(18) Pages: 4678-4681
  • Peer Reviewed
• [Journal Article] Asymmetr ic Total Synthesis of Neoxaline (2013)
  • Author(s): Ideguchi, Tetsuya; Yamada, Takeshi; Shirahata, Tatsuya; Hirose, Tomoyasu; Sugawara, Akihiro; Kobayashi, Yoshinori;?mura, Satoshi; Sunazuka, Toshiaki
  • Journal Title: Journal of the American Chemical Society Volume: 135(34) Pages: 12568-12571
  • Peer Reviewed
• [Journal Article] Towar d the Synthesis of Phomoidr ide D (2013)
  • Author(s): Murphy, Graham K.; Shirahata, Tatsuya; Hama, Naoto; Bedermann, Aaron; Dong, Ping; McMahon, Taravis C.; Twenter, Barry. M.; Spiegel, David A.; McDonald, Ivar. M.; Taniguchi, Nobuaki; Inoue, Munenori; Wood, John. L.
  • Journal Title: Journal of Organic Chemistry Volume: 78 Pages: 477-489
  • Peer Reviewed
• [Journal Article] Aogacillins A and B produced by Simplicillium sp. FKI-5985: new circumventors of arbekacin resistance in MRSA (2013)
  • Author(s): Takata, Keiko; Iwatsuki, Masato; Yamamoto, Tsuyoshi; Shirahata, Tatsuya; Nonaka, Kenichi; Masuma, Rokuro; Hayakawa, Yoichi; Hanaki, Hideaki; Kobayashi, Yoshinori; Petersson, George A.; Omura, Satoshi; Shiomi, Kazuro
  • Journal Title: Organic Letters Volume: 15 Issue: 18 Pages: 4678-4681
  • DOI: 10.1021/ol401975z
  • 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] Toward the Synthesis of Phomoidride D (2013)
  • Author(s): Murphy, G. K.; Shirahata, T.; Hama, N.; Bedermann, A.; Dong, P.; McMahon, T. C.; Twenter, B.. M.; Spiegel, D. A.; McDonald, I.. M.; Taniguchi, N.; Inoue, M.; Wood, J. L.
  • Journal Title: J. Org. Chem. Volume: 78 Issue: 2 Pages: 477-489
  • DOI: 10.1021/jo302353g
  • Peer Reviewed
• [Presentation] Synthesis and Effect of Nasal Administration on Nasal Anti-In?uenza Virus Antibody Titer against Second Nasal Inoculation of In?uenza HA Vaccine of Oleanolic acid Sapnonins (2013)
  • Author(s): Tatsuya Shirahata, Hiroaki Kiyohara, Nozomu Hirata, Masaki Yokoyama, Tatsuya Katsumi, Takashi Nishino, Kazuishi Makino, Takayuki Nagai, Haruki Yamada, Eisuke Kaji, Yoshinori Kobayashi
  • Organizer: International Conference on the Chemistry of Antibiotics and other bioactive compounds
  • Place of Presentation: (ICCA-13, Yamanashi, Japan)
  • Year and Date: 2013-09-25
• [Presentation] Synthesis and Effect of Nasal Administration on Nasal Anti-In?uenza Virus Antibody Titer against Second Nasal Inoculation of In?uenza HA Vaccine of Oleanolic acid Sapnonins (2013)
  • Author(s): Tatsuya Shirahata, Hiroaki Kiyohara, Nozomu Hirata, Masaki Yokoyama, Tatsuya Katsumi, Takashi Nishino, Kazuishi Makino, Takayuki Nagai, Haruki Yamada, Eisuke Kaji, Yoshinori Kobayashi
  • Organizer: Gordon Research Conferences Heterocyclic Comounds
  • Place of Presentation: (Newport, RI, USA)
  • Year and Date: 2013-06-17
• [Presentation] 1-OH糖を使用した脱水的グリコシル化による三糖合成 (2013)
  • Author(s): 白畑辰弥,小島麻実,照屋智子,鰻池将吾,横山将来,松尾淳一,牧野一石,砂塚敏明,梶英輔,大村智,小林義典
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜・パシフィコ横浜(横浜)
  • Year and Date: 2013-03-28
• [Presentation] Synthesis and Effect of Nasal Administration on Nasal Anti-Influenza Virus Antibody Titer against Second Nasal Inoculation of Influenza HA Vaccine of Oleanolic acid Sapnonins (2013)
  • Author(s): Tatsuya Shirahata, Hiroaki Kiyohara, Nozomu Hirata, Masaki Yokoyama, Tatsuya Katsumi, Takashi Nishino, Kazuishi Makino, Takayuki Nagai, Haruki Yamada, Eisuke Kaji, Yoshinori Kobayashi
  • Organizer: International Conference on the Chemistry of Antibiotics and other bioactive compounds
  • Place of Presentation: Yamanashi, Japan
• [Presentation] Synthesis and Effect of Nasal Administration on Nasal Anti-Influenza Virus Antibody Titer against Second Nasal Inoculation of Influenza HA Vaccine of Oleanolic acid Sapnonins (2013)
  • Author(s): Tatsuya Shirahata, Hiroaki Kiyohara, Nozomu Hirata, Masaki Yokoyama, Tatsuya Katsumi, Takashi Nishino, Kazuishi Makino, Takayuki Nagai, Haruki Yamada, Eisuke Kaji, Yoshinori Kobayashi
  • Organizer: Gordon Research Conferences Heterocyclic Comounds
  • Place of Presentation: Salve Regina University, Newport, RI, USA
• [Presentation] 白畑辰弥、小島麻実、照屋智子、鰻池将吾、横山将来、松尾淳一、牧野一石、砂塚敏明、梶英輔、 大村智，小林義典 (2013)
  • Author(s): 1-OH糖を使用した脱水的グリコシル化による三糖合成
  • Organizer: 日本薬学会第133年会
  • Place of Presentation: 横浜
• [Presentation] マイクロフローリアクターを利用した桂皮酸エステルを有するサポニンの合成研究 (2012)
  • Author(s): 白畑辰弥,勝見達也,横山将来,平田望,永井隆之,清原寛章,山田陽城,梶英輔,小林義典
  • Organizer: 第64回有機合成化学協会関東支部シンポジウム
  • Place of Presentation: 新潟・長岡科学技術大学(新潟、長岡)
  • Year and Date: 2012-12-01
• [Presentation] マイクロフローリアクターを利用した桂皮酸エステルを有するサポニンの合成研究 (2012)
  • Author(s): 白畑辰弥,勝見達也,横山将来,平田望,永井隆之,清原寛章,山田陽城,梶英輔,小林義典
  • Organizer: Glyco Tokyo 2012
  • Place of Presentation: 東京・慶應大学薬学部(東京)
  • Year and Date: 2012-11-17
• [Presentation] マイクロフローリアクターを利用した桂皮酸エステルを有するサポニンの合成研究 (2012)
  • Author(s): 白畑辰弥，勝見達也，横山将来，平田望, 永井隆之，清原寛章，山田陽城，梶英輔，小林義典
  • Organizer: Glyco Tokyo
  • Place of Presentation: 東京
• [Presentation] マイクロフローリアクターを利用した桂皮酸エステルを有するサポニンの合成研究 (2012)
  • Author(s): 白畑辰弥，勝見達也，横山将来，平田望, 永井隆之，清原寛章，山田陽城，梶英輔，小林義典
  • Organizer: 第64回有機合成化学協会関東支部シンポジウム
  • Place of Presentation: 長岡（新潟）
• [Remarks]
  • URL: http://www.pharm.kitasato-u.ac.jp/shoyaku/
• [Remarks] 北里大学薬学部生薬学教室ホームページ
  • URL: http://www.pharm.kitasato-u.ac.jp/shoyaku/