Synthesis and structure-activity relationship studies of aziridine-containing natural products with antimicrobial activity against multidrug-resistant bacteria

2023 Fiscal Year Final Research Report

• Project/Area Number: 22K14835
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 38040:Bioorganic chemistry-related
• Research Institution: The University of Tokyo
• Principal Investigator: Okamura Hironori 東京大学, 大学院農学生命科学研究科(農学部), 助教 (80845785)
• Project Period (FY): 2022-04-01 – 2024-03-31
• Keywords: アジリジン / 天然物 / 抗菌活性 / 全合成 / 構造活性相関

Outline of Final Research Achievements

Ficellomycin, an aziridine-containing natural product with a potent antibacterial activity against multidrug-resistant bacteria including MRSA is a promising candidate molecule as a novel antimicrobial agent. However, its structural rarity and undetermined absolute stereochemistry have stalled clinical development research. In this study, we aimed to develop an efficient synthetic method of ficellomycin and its analog vazabitide A to determine these stereochemistry. The key strategy of this study was "late-stage construction of unstable fused-aziridine structure of these natural products", but the preparation of its precursor was unexpectedly difficult. Based on this study, the fused-aziridine structure will be constructed by ring-closure metathesis of the intermediate of this study.

Free Research Field

天然物化学

Academic Significance and Societal Importance of the Research Achievements

薬剤耐性菌の出現以来、MRSAのように殆どの抗生物質が通用しない多剤耐性菌に対する新規抗菌剤の探索は世界規模での課題である。本研究では多剤耐性菌に対し有力な抗菌活性を示すficellomycinの世界に先駆けた合成と立体化学決定を目的として合成研究に取り組んだ。従来のアプローチでは手の届かない「極性官能基が組み込まれた縮環アジリジン構造」の取得には至らなかったものの、その前駆体である1,2-ジアミン構造の構築を達成した。今後、前駆体から目的とする構造を有する化合物が得られれば、ficellomycinのみならず強力な抗腫瘍活性を有する類縁天然物azinomycin類の合成への展望が拓ける。