Development of amphotericin B potenciators based on novel natural products

• Project/Area Number: 18K06554
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: Kitasato University
• Principal Investigator: Ohtawa Masaki 北里大学, 薬学部, 准教授 (70453503)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 天然物合成化学 / 活性増強物質 / 天然物合成 / アムホテリシンB / 創薬化学 / 天然有機化合物 / 有機合成化学 / 活性増強剤

Outline of Final Research Achievements

The total synthesis of FKI-4981B, a new potentiator of amphotericin B activity against Candida albicans, was achieved. Our research results enabled the access of all stereoisomers of FKI-4981B and the elucidation of the unknown absolute configuration of FKI-4981B.Furthermore, one of the stereoisomers is a better amphotericin B potentiator than FKI-4981B and is an excellent lead compound for the development of a novel amphotericin B potentiator.

Academic Significance and Societal Importance of the Research Achievements

Amphotericin B (AMPB) は深在性真菌症に対する治療薬の第一選択であるものの、最大の欠点は副作用の重篤さである。そのため新たなAMPBの副作用軽減策の開発が急務である。北里大学薬学部において見出されたFKI-4981Bならびにshidoamideは天然由来のAMPB活性増強物質であり、これらをリード化合物する、これまでにないAMPBの副作用軽減する薬剤開発が望まれる。本研究成果にてそれを可能とする基盤を築くことができ、今後の研究により有望なAMPB活性増強物質が創出されることが期待される。

Research Products

• [Journal Article] One-Pot γ-Lactonization of Homopropargyl Alcohols via Intramolecular Ketene Trapping (2021)
  • Author(s): Yamane Daichi、Tanaka Haruna、Hirata Akihiro、Tamura Yumiko、Takahashi Daichi、Takahashi Yusuke、Nagamitsu Tohru、Ohtawa Masaki
  • Journal Title: Organic Letters Volume: 23 Issue: 7 Pages: 2831-2835
  • DOI: 10.1021/acs.orglett.1c00840
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Synthetic, Mechanistic, and Biological Interrogation of Ginkgo biloba Chemical Space En Route to (?)-Bilobalide (2020)
  • Author(s): Demoret Robert M.、Baker Meghan A.、Ohtawa Masaki、Chen Shuming、Lam Ching Ching、Khom Sophia、Roberto Marisa、Forli Stefano、Houk Kendall N.、Shenvi Ryan A.
  • Journal Title: Journal of the American Chemical Society Volume: 142 Issue: 43 Pages: 18599-18618
  • DOI: 10.1021/jacs.0c08231
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Repair of DNA damage induced by the novel nucleoside analogue CNDAG through homologous recombination (2020)
  • Author(s): Liu Xiaojun、Jiang Yingjun、Nowak Billie、Ichikawa Satoshi、Ohtawa Masaki、Matsuda Akira、Plunkett William
  • Journal Title: Cancer Chemotherapy and Pharmacology Volume: 85 Issue: 4 Pages: 661-672
  • DOI: 10.1007/s00280-020-04035-x
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Total Synthesis and Absolute Configuration of Simpotentin, a Potentiator of Amphotericin B Activity (2019)
  • Author(s): Ohtawa Masaki、Shimizu Eri、Saito Atsushi、Sakamoto Sayuri、Waki Ai、Kondo Ariko、Yagi Akiho、Uchida Ryuji、Tomoda Hiroshi、Nagamitsu Tohru
  • Journal Title: Organic Letters Volume: 21 Issue: 14 Pages: 5596-5599
  • DOI: 10.1021/acs.orglett.9b01945
  • Peer Reviewed
• [Presentation] 構造の複雑な天然物の効率的な合成法の構築を目指して (2021)
  • Author(s): 大多和正樹
  • Organizer: 日本薬学会第141年会
  • Invited
• [Presentation] Amphotericin B活性増強作用を有するsimpotentinの全合成と絶対立体配置の決定 (2020)
  • Author(s): 大多和正樹、李大葵、内田龍児、供田洋、長光亨
  • Organizer: 日本薬学会第140年会
• [Presentation] Total synthesis and absolute configuration of simpotentin, a potentiator of amphotericin B activity (2019)
  • Author(s): Masaki Ohtawa, Ryuji Uchida, Hiroshi Tomoda, Tohru Nagamitsu
  • Organizer: 258th ACS National Meeting & Exposition
  • Int'l Joint Research
• [Presentation] Simpotentinの全合成と絶対立体配置の決定 (2018)
  • Author(s): 大多和 正樹、長光 亨
  • Organizer: 第41回白金シンポジウム
• [Presentation] Amphotericin B活性増強作用を有するsimpotentinの全合成と絶対立体配置の決定 (2018)
  • Author(s): 大多和正樹、清水恵里、齋藤淳、李大葵、近藤あり子、 八木瑛穂、小林啓介、内田龍児、供田洋、長光亨
  • Organizer: 第44回反応と合成の進歩シンポジウム