Design, Synthesis and Functional Analysis of Ion-Channel-Forming Molecules Based on Polytheonamide Structure

• Project/Area Number: 15H06156
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Chemical pharmacy
• Research Institution: The University of Tokyo
• Principal Investigator: Itoh Hiroaki 東京大学, 大学院薬学系研究科(薬学部), 助教 (20758205)
• Project Period (FY): 2015-08-28 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 固相合成 / 有機化学 / 合成化学 / ペプチド / イオンチャネル / 脂質

Outline of Final Research Achievements

Polytheonamide B is an ion-channel-forming 48-mer natural peptide that displays extraordinarily potent cytotoxicity. This study focuses on establishment of highly efficient solid-phase synthetic strategy for detailed functional and biological investigations of polytheonamide B and its analogues. Novel strategy of protective groups for component amino acids enabled full solid-phase total synthesis of polytheonamide B and its analogues. The newly established synthetic strategy significantly reduced the number of solution-phase synthetic steps and HPLC purification steps, leading to the efficient and facile synthesis of the total structure of polytheonamide B.

Research Products

• [Journal Article] Total Synthesis and Functional Evaluation of Fourteen Derivatives of Lysocin E: Importance of Cationic, Hydrophobic, and Aromatic Moieties for Antibacterial Activity (2016)
  • Author(s): T. Kaji, M. Murai, H. Itoh, J. Yasukawa, H. Hamamoto, K. Sekimizu, M. Inoue
  • Journal Title: Chem. Eur. J. Volume: 22 Issue: 47 Pages: 16912-16919
  • DOI: 10.1002/chem.201604022
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] The Total Synthesis and Functional Evaluation of Fourteen Stereoisomers of Yaku’amide B. The Importance of Stereochemistry for Hydrophobicity and Cytotoxicity (2016)
  • Author(s): H. Mutoh, Y. Sesoko, T. Kuranaga, H. Itoh, M. Inoue
  • Journal Title: Org. Biomol. Chem. Volume: 14 Issue: 18 Pages: 4199-4204
  • DOI: 10.1039/c6ob00640j
  • Peer Reviewed / Open Access
• [Journal Article] Dual Chemical Modification of Polytheonamide Mimic: Rational Design and Synthesis of Ion-Channel-Forming 48-mer Peptides with Potent Cytotoxicities (2016)
  • Author(s): A. Hayata, H. Itoh, S. Matsutaka, M. Inoue
  • Journal Title: Chem. Eur. J. Volume: 22 Issue: 10 Pages: 3370-3377
  • DOI: 10.1002/chem.201504632
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] ポリセオナミドBの固相全合成 (2017)
  • Author(s): 早田敦、伊藤寛晃、井上将行
  • Organizer: 日本薬学会 第137年会
  • Place of Presentation: 東北大学(宮城県・仙台市)
  • Year and Date: 2017-03-24
• [Presentation] WAP-8294A2の全合成および機能解析 (2017)
  • Author(s): 徳本皓太郎、伊藤寛晃、井上将行
  • Organizer: 日本薬学会 第137年会
  • Place of Presentation: 東北大学(宮城県・仙台市)
  • Year and Date: 2017-03-24
• [Presentation] ヤクアミドBの固相全合成 (2017)
  • Author(s): 神谷光一、山下智也、伊藤寛晃、井上将行
  • Organizer: 日本薬学会 第137年会
  • Place of Presentation: 東北大学(宮城県・仙台市)
  • Year and Date: 2017-03-24
• [Presentation] 抗菌ペプチド中分子ライソシンEの構造機能相関研究 (2017)
  • Author(s): 伊藤寛晃、加治拓也、井上将行
  • Organizer: 第3回新学術領域「中分子戦略」若手シンポジウム
  • Place of Presentation: 聖護院御殿荘(京都府・京都市)
  • Year and Date: 2017-03-07
• [Presentation] Total Synthesis and Functional Evaluation of Fourteen Derivatives of Lysocin E (2016)
  • Author(s): Hiroaki Itoh, Takuya Kaji, Masayuki Inoue
  • Organizer: The 16th Tateshina Conference on Organic Chemistry
  • Place of Presentation: 蓼科フォーラム(長野県・茅野市)
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] Staudingerライゲーションを用いたヤクアミドBの合成研究 (2016)
  • Author(s): 山下智也、伊藤寛晃、井上将行
  • Organizer: 日本薬学会 第136年会
  • Place of Presentation: パシフィコ横浜(横浜)
  • Year and Date: 2016-03-26
• [Presentation] Syntheses and Structure-Function Relationship Study of Lysocins (2016)
  • Author(s): Takuya Kaji, Motoki Murai, Hiroaki Itoh, Hiroshi Hamamoto, Masayuki Inoue
  • Organizer: The 8th Takeda Science Foundation Symposium on PharmaSciences
  • Place of Presentation: 武田薬品工業研修所(大阪)
  • Year and Date: 2016-01-21
• [Presentation] Enhancement of Bioactivity by Dual Chemical Modification of Polytheonamide Mimic (2015)
  • Author(s): Atsushi Hayata, Hiroaki Itoh, Shoko Matsutaka, Masayuki Inoue
  • Organizer: LMU-UTOKYO SYMPOSIUM 2015
  • Place of Presentation: Munich, Germany
  • Year and Date: 2015-10-27
  • Int'l Joint Research