14-epi-19-nortachysterolの開発と,ヒトのビタミンD受容体に対する前例のない結合構成
Daisuke Sawada1, Yuya Tsukuda, Hiroshi Saito
1Faculty of Pharmaceutical Sciences, Teikyo University, 1091-1, Suwarashi, Sagamihara, Kanagawa 252-5195, Japan.
Journal of the American Chemical Society
|April 20, 2011
まとめ
研究者らは新しい14-epi-19-nortachysterol誘導体を合成し,それらは安定し,ビタミンD受容体 (VDR) に強く結合することを発見しました. この研究は,ユニークな結合構成を持つ安定したタキステロール類の同類体を初めて分離したものです.
科学分野:
- 合成有機化学 合成有機化学とは
- エンドクリノロジー エンドクリノロジー
- 構造生物学 構造生物学とは
背景:
- プレビタンミンD ((3) とその誘導体は,カルシウムホメオスタシスと細胞プロセスにおいて極めて重要です.
- タチステロルの類型は知られているが,安定性が欠けていることが多い.
- ビタミンD受容体 (VDR) リガンドの相互作用を理解することは,治療薬の開発の鍵です.
研究 の 目的:
- 新規の14-epi-19-norprevitamin D(3) デリバティブを合成し,特徴づけること.
- これらの新しい化合物の安定性とVDR結合親和性を調査する.
- 人間のVDR (hVDR) のリガンド結合ポケット内のこれらの類似体の結合構成を解明する.
主な方法:
- 14-epi-19-norprevitamin D ((3) の化学合成と,その後のC6,7-cis/transのイソメリゼーション.
- 合成した14-epi-19-nortachysterol誘導体の分離と浄化.
- 化合物の安定性およびhVDRへの結合親和性の評価は,確立された生化学的測定を用いて行われます.
- hVDR内のトリエンの構成を決定するための構造分析.
主要な成果:
- 14-epi-19-nortachysterol誘導体の合成に成功しました.
- 顕著な安定性と,合成アナログに対する強力なVDR結合親和性が実証されています.
- 安定したタキステロルの類型剤の最初の分離が報告されました.
- 前例のない結合構成 (C5,6-s-トランスとC7,8-s-トランストリエン) がhVDRリガンド結合ポケットで観察されました.
結論:
- 強力なVDR結合を持つ安定したタキステロールの類型が合成されています.
- これらの新しい化合物は,天然のビタミンD化合物とは異なる,hVDR内のユニークな結合モードを示しています.
- この発見は,VDRを標的とする治療法を設計し,適合した結合特性を持つための新たな道を開く.
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