Synthesis of the lead compound of PPI inhibitor, Dityromycin

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K05059
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 33020:Synthetic organic chemistry-related
• Research Institution: Kitasato University
• Principal Investigator: Sunazuka Toshiaki 北里大学, 感染制御科学府, 教授 (30226592)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 抗生物質 / 嫌気性菌 / 大腸炎治療薬 / PPI阻害剤 / 全合成 / 絶対立体化学構造 / 微生物培養

Outline of Final Research Achievements

As the retrosynthesis of dityromycin, we divided it into 3 fragments in convergent manner; the cyclic isodityrosin core as a northern part, highly oxidized dehydroisoleucine containing peptide as a southern part, and the remaining linear peptide as an eastern part.
Our synthetic endeavor was commenced with material pushing of each fragments on gram scale along the synthetic route we established before. As a side note, we improved the yield and suppressed the epimerization of the eastern part by capitalizing the Fm protecting group. En route to dityromycin, all fragments were condensed and afforded decapeptide which contains all amino acid components of dityromycin on gram scale. After numerous optimization and tunings, we obtained macrocyclized product on gram scale by sequential Alloc/Allyl cleavage, excessive EDCI mediated macrocyclization.

Free Research Field

天然物化学、有機合成化学

Academic Significance and Societal Importance of the Research Achievements

世界で多くの問題となっている耐性菌に対してこれまでと違うメカニズムで抗菌活性を示す新規抗生物質であるDityromycinに関して、まず絶対構造を明らかにし、そしてさらに簡便な合成ルートを確立することにより、様々な類縁体を作ることによりこれまでにない新規薬剤開発に繋がる。そしてこのDityromycinは、タンパクとタンパクとの結合を特異的に阻害する薬剤であるので、クライオ電子顕微鏡でどのように結合するかを明らかにすることにより特異的な薬剤開発に繋がり、将来の耐性菌問題に利用されることが多いに期待される。