Development of nuclear receptor PXR antagonists from marine natural products

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07116
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47050:Environmental and natural pharmaceutical resources-related
• Research Institution: Okayama University
• Principal Investigator: KUBOTA Takaaki 岡山大学, 医歯薬学域, 教授 (60399954)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 核内受容体 / Pregnane X Receptor / アンタゴニスト / 海洋生物 / 海綿動物 / 渦鞭毛藻 / 海産天然物 / 天然有機化合物

Outline of Final Research Achievements

The search for new marine natural products having affinity for nuclear receptor PXR from marine organisms was performed. As a result, new manzamine-related alkaloids zamamiphidins B and C were isolated from an Amphimedon sp. marine sponge and their structures, including the relative configurations were elucidated. While new bromotyrosine alkaloids ma’edamines E and F were isolated from a Subrea sp. marine sponge and their structures were elucidated. In addition to these, three new marine natural products were isolated from dinoflagellates and eight from sponges, and their structures were elucidated, including their partial stereochemistry. The stereochemistry of these marine natural products were currently being analyzed. In addition, the activity of new and known compounds against PXR being evaluated.

Free Research Field

天然物化学

Academic Significance and Societal Importance of the Research Achievements

薬物代謝は異物を体外に排出する重要な解毒機構であるが、一方で異物とみなした薬物の薬効を減弱させてしまう。核内受容体PXRは、薬物代謝酵素や薬物トランスポーターの発現を誘導し、薬物代謝を亢進させることにより様々な薬物の薬効を減弱させる。PXRの機能を阻害すれば薬物の薬効減弱を防ぐことができるが、選択的な阻害剤は合成化合物のSPA70のみであるため、新しいタイプの阻害剤の開発が求められている。本研究により渦鞭毛藻や海綿動物から15個の新規化合物が得られた。これらの化合物は既存のPXR阻害剤とは異なる化学構造を有していることから、新たなPXR阻害剤のシーズとなる可能性を秘めている。