ハロゲン結合形成によって媒介されるLeishmaniaトポイソメラーゼIB酵素を効果的に阻害する抗リーシュマニア作用を持つ新しいブロム化ビニル脂肪酸の合成
Néstor M Carballeira1, Denisse Alequín2, Leilani M Lotti Diaz2
1University of Puerto Rico, Río Piedras Campus, 17 Ave Universidad STE 1701, San Juan, PR 00925-2537, USA, Tel.: (787)-764-0000 ext, 88561.
まとめ
海産脂肪酸のハロゲン分子は 抗リーシュマニア剤として有望です 新しい合成化合物は,リーシュマニアDNAトポイソメラーゼIBを選択的に抑制し,新しい治療法を提供しています.
科学分野:
- 薬剤化学
- 有機合成
- 寄生虫学
背景:
- 海産天然製品,特にスポンジは,しばしばビニルハロゲン分子を含んでいる.
- これらの海洋化合物,特に脂肪酸の抗リーシュマニアの可能性は,ほとんど未知のままです.
- リーシュマニアは重要な寄生虫性疾患であり,新たな治療戦略が必要である.
研究 の 目的:
- 新しい2アルリル3ハロ2ノンアデセノ酸を合成する
- 合成された化合物を*Leishmania*DNAトポイソメラーゼIB (*L*TopIB) の阻害剤として評価する.
- ヒトトポイソメラーゼIB (hTopIB) に対する抑制の選択性と, *Leishmania* 寄生虫に対する細胞毒性を評価する.
主な方法:
- 2-アリル-3-ブロモ-2*E*-ノンアデセノ酸 (1a) と2-アリル-3-クロロ-2*E*-ノンアデセノ酸 (2a) のパラジウム触媒によるハロアリレーションによる合成
- 2-ドデシノ酸から短鎖類 (1b,2b) の合成
- *L*TopIBとhTopIBに対する酵素阻害アッセイ, *Leishmania infantum*アマスティゴートとプロマスティゴートに対する細胞毒性アッセイ,および計算による結合エネルギー分析.
主要な成果:
- 化合物1aと2aは,総収量57~83%で合成された.
- 化合物1aは*L*TopIB (EC50 = 7 μM) の強力な阻害と*L.インファントム*アマスティゴートに対する好ましい細胞毒性 (EC50 = 2.5 μM) を示した.
- 抑制は1a > 2- NDA > 2a >> 1b ≈ 2bの順に続き,1aと2aはギマテカン独立のメカニズムで作用し,ハロゲン結合によって合理化された.
結論:
- 合成された2 - アリル - 3 - ハロ - 2 ノンアデセノ酸は,有望な抗リーシュマニア候補である.
- 化合物1aは, *L*TopIBの選択的阻害と, *Leishmania*アマスティゴートに対する強力な細胞毒性を示しています.
- この発見は,Leishmania* DNAトポイソメラーゼIBを標的とするハロゲン脂肪酸の治療の可能性を強調しています.
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