Construction of a natural product library composed of azepine alkaloids and determination of their absolute configuration by VCD spectroscopy.

2018 Fiscal Year Final Research Report

• Project/Area Number: 16K08308
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Natural medicines
• Research Institution: Tokyo University of Pharmacy and Life Science
• Principal Investigator: HITOTSUYANAGI Yukio 東京薬科大学, 薬学部, 教授 (80218726)
• Research Collaborator: FUKAYA Haruhiko
• Project Period (FY): 2016-10-21 – 2019-03-31
• Keywords: 赤外円二色性スペク トル / 化合物ライブラリ / アルカロイド / 環状ペプチド / 密度汎関数理論 / Stemona tuberosa / Rubia cordifolia

Outline of Final Research Achievements

Eleven new alkaloids were isolated from the roots of Stemona tuberosa to create a natural products library composed of alkaloids possessing an azepine ring, which is often found in the structures of important synthetic drugs. I found conditions to convert the chemically labile azepine alkaloid into its stable N-oxide to restrict the conformational freedom of the parent alkaloid. Vibrational circular dichroism (VCD) spectroscopy was applied to determine the absolute configuration of RA-VII, a bicyclic hexapeptide with an 18-membered ring, indicating that the VCD spectroscopy is applicable to macrocyclic peptides. Three new RA-series cyclopeptide alkaloids were isolated from the roots of Rubia cordifolia and their structures were determined. Conformational analysis and the DFT calculation of those new peptides revealed that the N-methyl group at Tyr-5 is important for RA-VII to preferentially adopt the active conformation.

Free Research Field

天然物化学

Academic Significance and Societal Importance of the Research Achievements

Stemona tuberosaより見出したアゼピン骨格を有する新規アルカロイド類はいずれも新奇性の高いユニークな構造を有しており、医薬品開発の活性スクリーニングに供する構造多様性に富む天然化合物ライブラリーを構築するうえで、重要度が高い構成要素となるものである。また、赤外円二色性スペクトル法を分子量の大きいマクロ環状ペプチドアルカロイドに適応し、非晶質性中分子化合物の絶対配置決定に本法が応用できることを示した。