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保護されていないペプチドのマクロサイクリングのための窒素アリレーション
Guillaume Lautrette1, Fayçal Touti1, Hong Geun Lee1
1Department of Chemistry, Massachusetts Institute of Technology , Cambridge, Massachusetts 02139, United States.
Journal of the American Chemical Society
|June 23, 2016
まとめ
窒素アリレーションを用いてマクロサイクリックペプチドを作る 新しい方法を開発しました このアプローチにより,安定した化合物が得られ,強力なp53ペプチド阻害剤が成功しました.
科学分野:
- 有機化学
- 薬剤化学
- ペプチド合成
背景:
- マクロサイクルペプチドは,その安定性と生物学的活性により,薬剤発見において重要である.
- マクロサイクルペプチド合成の現在の方法は,しばしば厳しい条件または保護群を必要とします.
- 新種のペプチド療法へのアクセスには 温和で効率的な合成経路の開発が不可欠です
研究 の 目的:
- 窒素アリレーションによるマクロサイクリックペプチドの合成のための効率的で穏やかな方法を確立する.
- この新しい方法論の範囲と限界を様々な前駆体を使って調査する.
- 生物学的に重要なペプチド阻害剤の合成のために開発された方法を適用する.
主な方法:
- 保護されていないペプチド前駆体による窒素アリレーションは,様々な電ophilesと lysine-based nucleophilesを用いて行われます.
- 反応効率を評価するために14の変種を含むマクロサイクライゼーションスキャン.
- N-アリルとS-アリル結合マクロサイクルを比較した安定性研究
- MDM2のp53ペプチド阻害剤を合成する方法の適用
主要な成果:
- マクロサイクリックペプチドの高収量形成は,穏やかな条件下で達成された.
- N- アリルマクロサイクル製品は,S- アリル類に比べ,塩基および酸化分解に対する安定性が向上した.
- この方法は,p53ペプチド阻害剤に適用され,ナノモラー結合剤が得られました.
- 結果として生成されたN- アリルマクロサイクル阻害剤は,タンパク質分解の安定性と細胞の透過性を改善した.
結論:
- 記述された窒素アリレーション方法は,保護されていない前駆体からマクロサイクルペプチドへの効率的で穏やかな経路を提供します.
- この方法論は,安定した強力なペプチドベースの治療法を生み出すための貴重なツールを提供します.
- N-アリルマクロサイクルp53阻害剤の改善された性質は,薬剤発見におけるこのアプローチの可能性を強調しています.
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