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Split-and-pool Synthesis and Characterization of Peptide Tertiary Amide Library
Published on: June 20, 2014
ラモプラニンA2とラモプラノースアグリコンの総合成
Wanlong Jiang1, Jutta Wanner, Richard J Lee
1Department of Chemistry and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA.
Journal of the American Chemical Society
|February 13, 2003
まとめ
この研究では,ラモプラニンA2とそのアグリコンの融合合成について詳細に説明しています. 主なステップは,3つのサブユニットを準備し,それらを結合し,循環してデプシペプチドコアを形成し,将来の抗菌類のアナログの開発を可能にします.
科学分野:
- 有機化学 オーガニック・ケミストリー
- 薬用化学 薬用化学について
- 合成生物学 合成生物学とは
背景:
- ラモプラニンA2は,重要な抗菌作用を有する複雑なグリコペプチド抗生物質です.
- ラモプラニンA2とそのアグリコンの総合成は,その複雑な構造のためにかなりの課題を提示します.
- この合成を理解することは,新しい抗菌剤の開発に不可欠です.
研究 の 目的:
- ラモプラニンA2とそのアグリコンのコンバージェントトータル合成の完全な詳細を明らかにする.
- 抗菌剤の潜在的応用を持つ同類剤の製造に適した合成経路を確立する.
- デプシペプチド核の効率的な形成のためのマクロサイクライゼーション戦略を調査する.
主な方法:
- 3つの主要なサブユニット:ヘプタペプチド,ペンタデプシペプチド,ペンタペプチドを含む収束合成.
- ペンタデプシペプチド骨幹エステルのl-threo-beta-hydroxyasparagineの非対称合成について.
- ラセミゼーションを最小限に抑え,阻害されたアルコールをエステル化する最適化されたエステル化条件 (EDCI,DMAP,0°C)
- 戦略的な結合場所の選択により,収束を最大化し,後期的なレース化を防止します.
- 2つのマクロサイクライゼーション部位 (Phe9−dOrn10とGly14−Leu15) を調査し,49個の環の閉塞を図る.
- デプシペプチドエステルサブユニットとAsn ((1) サイドチェーン.の遅い段階の組み込み.
主要な成果:
- 3つの主要なサブユニットの準備と順次結合が成功しました.
- アグリコンの49個のデプシペプチド核の効率的な形成.
- 高収量 (89%) のマクロサイクリングがPhe{9) -d-Orn{10) 部位で行われ,ベータシート前編成による可能性が高い.
- アナログ合成に適した,Gly(14) -Leu(15) 部位での容認可能な収量 (40-50%) のマクロサイクリング.
- アナログ開発のための後期改変の実現可能性が実証されています.
結論:
- ラモプラニンA2アグリコンの頑丈で収束した全合成が達成されました.
- 開発された合成戦略は,複雑なマクロサイクリックデプシペプチドコアの効率的な構築を可能にします.
- この方法論は,後期的な改変によって,新しい,強力な抗菌類類にアクセスするためのプラットフォームを提供します.
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