Development of anti-XDR-TB leads based on catalytic asymmetric synthesis and chemical biology

• Project/Area Number: 26460168
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Microbial Chemistry Research Foundation
• Principal Investigator: WATANABE Takumi 公益財団法人微生物化学研究会, 微生物化学研究所, 部長 (80270544)
• Co-Investigator(Renkei-kenkyūsha): ISHIZAKI Yoshimasa (公財)微生物化学研究会, 微生物化学研究所 第2生物活性研究部, 主任研究員 (10414103) ; UMEZAWA Yoji (公財)微生物化学研究会, 微生物化学研究所 分子構造解析部, 部長 (60160313) ; SAKAMOTO Shuichi (公財)微生物化学研究会, 微生物化学研究所 沼津支所, 上級研究員 (60346070)
• Research Collaborator: Gandamala Ravi (公財)微生物化学研究会, 微生物化学研究所 有機合成研究部, 博士研究員 ; Wang Lu (公財)微生物化学研究会, 微生物化学研究所 有機合成研究部, 博士研究員
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 触媒的不斉合成 / ケミカルバイオロジー / XDR-TB / 抗結核薬 / 構造活性相関

Outline of Final Research Achievements

Initially, caprazamycin derivatives which is not accessible by semi-synthetic strategy starting from naturally-occurring captazamycin were prepared based on the catalytic asymmetric synthetic route to caprazol and caprazamycin; caprazol derivatives with longer aliphatic side chain installed on one of the nitrogen atoms embedded in the seven-membered lactam core were successfully synthesized.
Then, catalytic asymmetric synthesis of CPZEN-45 was accomplised. In the synthetic route, a complex comprising Zn and chiral linked-BINOL ligand was found to be effective for the aldol reaction to construct the beta-hydroxyamino acid substructure to show excellent diastereoselectivity.

Research Products

• [Journal Article] SYNTHESIS OF CAPRAZAMYCINS AND RELATED NATURAL PRODUCTS (2017)
  • Author(s): Takumi Watanabe
  • Journal Title: Heterocycles Volume: 95 Issue: 2 Pages: 662-693
  • DOI: 10.3987/rev-16-sr(s)5
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Catalytic Asymmetric Synthesis of CPZEN-45 (2016)
  • Author(s): Takeuchi, T.; Abe, H.; Watanabe, T.; Shibasaki, M.
  • Journal Title: Tetrahedron Lett. Volume: 57 Issue: 26 Pages: 2901-2904
  • DOI: 10.1016/j.tetlet.2016.05.072
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Synthesis of caprazamycin B (2015)
  • Author(s): Hikaru Abe, Purushothaman Gopinath, Gandamala Ravi, Lu Wang, Takumi Watanabe, Masakatsu Shibasaki
  • Journal Title: Tetrahedron Lett. Volume: 印刷中 Issue: 24 Pages: 3782-3785
  • DOI: 10.1016/j.tetlet.2015.04.065
  • Peer Reviewed
• [Presentation] 抗超多剤耐性結核化合物CPZEN-45の触媒的不斉全合成 (2016)
  • Author(s): 竹内倫文、阿部光、渡辺匠、柴﨑正勝
  • Organizer: 第110回有機合成シンポジウム
  • Place of Presentation: 早稲田大学国際会議場（東京都新宿区）
  • Year and Date: 2016-11-10
• [Presentation] Catalytic asymmetric synthesis of biologically active natural products (2016)
  • Author(s): Takumi Watanabe
  • Organizer: Stereochemistry 2016
  • Place of Presentation: Hotel Grand Mercure Sao Paulo Ibirapuera (Sao Paulo, Brazil)
  • Year and Date: 2016-08-18
  • Int'l Joint Research / Invited
• [Presentation] 抗超多剤耐性結核化合物CPZEN-45の合成研究 (2016)
  • Author(s): 竹内 倫文，渡辺 匠，柴崎 正勝
  • 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: 2016-03-29
• [Presentation] Synthesis of anti-TB and anti-cancer natural products (2015)
  • Author(s): Takumi Watanabe
  • Organizer: International Conference on “Current Challenges in Drug Discovery Research"
  • Place of Presentation: Malaviya National Institute of Technology (Jaipur, India)
  • Year and Date: 2015-11-23
  • Int'l Joint Research / Invited
• [Presentation] Catalytic Asymmetric Synthesis of Caprazamycin B and Caprazol (2015)
  • Author(s): Takumi Watanabe, Purushothaman Gopinath, Lu Wang, Hikaru Abe, Gandamala Ravi, Takashi Masuda, Masakatsu Shibasaki
  • Organizer: 6th International Symposium on Advances in Synthetic and Medicinal Chemistry
  • Place of Presentation: Weizmann Institute (Rehovot, Israel)
  • Year and Date: 2015-11-18
  • Int'l Joint Research
• [Presentation] カプラザマイシン類の合成研究：（＋）-カプラゾールの触媒的不斉全合成 (2015)
  • Author(s): Gopinath Purushothaman，阿部 光，Lu Wang，Ravi Gandamala，舛田岳史，渡辺 匠，柴﨑正勝
  • Organizer: 日本薬学会第135年会
  • Place of Presentation: デザイン・クリエイティブセンター神戸，神戸市
  • Year and Date: 2015-03-27
• [Presentation] カプラザマイシン類の合成研究：(+)-カプラゾールの触媒的不斉全合成 (2014)
  • Author(s): 渡辺 匠，Gopinath Purushothaman，Lu Wang，阿部 光，Ravi Gandamala，舛田岳史，柴崎正勝
  • Organizer: 第56回天然有機化合物討論会
  • Place of Presentation: 高知県立県民文化ホール，高知市
  • Year and Date: 2014-10-16
• [Presentation] Catalytic Asymmetric Total Synthesis of (+)-Caprazol (2014)
  • Author(s): Takumi Watanabe, Purushothaman Gopinath, Lu Wang, Hikaru Abe, Takashi Masuda, Gandamala Ravi and Masakatsu Shibasaki
  • Organizer: 5th EuCheMS Chemistry Congress
  • Place of Presentation: Wow Convension Center Istanbul, Istunbul, Turkey
  • Year and Date: 2014-09-02
• [Remarks] IMC 微生物化学研究所
  • URL: http://www.bikaken.or.jp/