2-ベンザミドエチル群 - オリゴヌクレオチド合成のための新しいタイプのリン酸保護群
1Department of Medicinal Chemistry, Isis Pharmaceuticals, Inc., 2292 Faraday Ave., Carlsbad, California 92009, USA. aguzaev@isisph.com
Journal of the American Chemical Society
|July 18, 2001
まとめ
オリゴヌクレオチド合成のための新しいフォスフォラミジット保護群は,調整可能な脱保護率を提供し,一部は数分で除去されます. これにより,核酸に損傷を与えることなく,天然および改変されたオリゴヌクレオチドの効率的な合成が可能になります.
科学分野:
- 有機化学 オーガニック・ケミストリー
- 核酸化学 核酸化学について
- 合成化学 合成化学とは
背景:
- オリゴヌクレオチドの効率的な合成には,強力な保護グループ戦略が必要です.
- 既存のフォスフォラミドイトの保護群は,安定性と減保護運動性が変動する.
- オリゴヌクレオチド合成を最適化するために,新しい保護群が必要である.
研究 の 目的:
- P (III) 保護による新しい5'-O-(4,4'-ジメトキシトリチル) チミジン・フォスフォラミド酸塩を合成し,評価する.
- これらの新しい保護群の減保護運動とメカニズムを調査する.
- オリゴヌクレオチドとその類似体の合成におけるこれらの構成要素の有用性を評価する.
主な方法:
- 11種類の新しい2ベンザミドエタノールで保護されたフォスフォラミド酸塩の合成.
- これらのフォスフォラミド酸塩を合成20メルのオリゴヌクレオチオチドおよびフォスフォロチオ酸ナログに組み込む.
- 濃縮されたアンモニアム水酸化物を様々な温度で使用して,デプロテクションの運動学的研究.
- モデル・フォスフォトトリエステルを用いた脱保護プロセスのメカニズム的調査.
主要な成果:
- 保護グループの置換パターンに応じて,脱保護時間は25分から48時間まで変化しました.
- 2-[N-イソプロピル-N-(4-メトキシベンゾイル) アミノ]エチル (H) とオメガ-(チオノベンゾイラミノ) アルキル (I と K) 群は,最も迅速な除去を示しました.
- 新しいリン酸化反応剤とフォスフォラミジットの構成要素が合成され,オリゴヌクレオチド合成に成功して適用されました.
- デプロテクションメカニズムは,オリゴヌクレオチドと反応しない安定した2オクサゾリニウムカチオン中間物のpH依存の形成を明らかにした.
結論:
- 核酸間フォスフォディエステル群を保護するための多用途戦略が開発されました.
- 新しい保護群は,調整可能な脱保護率を提供し,効率的なオリゴヌクレオチド合成を可能にします.
- この方法論は, (III) および (V) 化合物を含む合成有機化学における応用の可能性を秘めています.
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