Development of disulfide-driven cyclic peptide synthesis based on Npys derivatives

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K16324
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 47010:Pharmaceutical chemistry and drug development sciences-related
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: Taguchi Akihiro 東京薬科大学, 薬学部, 講師 (40707311)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: ジスルフィド / 環状ペプチド / 3-ニトロ-2-ピリジンスルフェン酸エステル / 創薬化学 / ペプチド合成 / 固相合成 / 有機化学

Outline of Final Research Achievements

We have developed an on-resin disulfide-driven cyclic peptide synthesis method using 3-nitro-2-pyridinesulfenates. First, as a key reaction in this method, the active disulfide formation at side chain of the cysteine residue by sulfenates was investigated. As a result, it found that the reaction was efficient when the derivative Npys-OPh(pF) was used. Furthermore, in order to demonstrate the concept of this method, we tried the synthesis of oxytocin using two fragments divided from its sequence. A one-pot synthesis of oxytocin has been achieved by on-resin reactions including a disulfide exchange reaction between two fragments and an intramolecular amide bond formation.

Free Research Field

創薬化学

Academic Significance and Societal Importance of the Research Achievements

近年、環状ジスルフィドペプチドが医薬品候補化合物として注目を集めている。スルフェン酸エステルのジスルフィド形成能に立脚したペプチド合成法の構築は、環状ペプチドの効率的合成に繋がり、有機化学、ペプチド・タンパク質化学において学術的貢献が期待できる。また、本手法の自動化により、環状ペプチドのプロセス合成および効率的自動合成法の提供も可能と考えられる。