ダイオキソリガンドの電子構造を調節することによって,Ru (II) ポリピリジル複合体の細胞毒性を増加させる
Anna Notaro, Marta Jakubaszek1, Nils Rotthowe2
1Institut Curie, PSL University, CNRS, UMR 144, F-75005 Paris, France.
Journal of the American Chemical Society
|February 29, 2020
まとめ
この研究では,抗がん剤としてのルテニウム複合体を調査し,電子提供群 (1-4複合体) の細胞毒性が電子取り除く群 (5-6複合体) の細胞毒性より高いことを発見した. コンプレックス1は高効率で複数の細胞を標的とするので,有望な化学療法候補です.
科学分野:
- 協調化学
- 薬用無機化学
- 化学生物学
背景:
- ルテニウム複合体は,抗がん薬候補として有意な可能性を示しています.
- 薬剤の効能とターゲティングを最適化するために,構造と活性との関係は極めて重要です.
- Ru-sq複合体のセミキノナートリガンドは,導出のためのプラットフォームを提供します.
研究 の 目的:
- 新しいルテニウム-カテコラート複合体の構造-活性関係 (SAR) 研究を行う.
- 複合体特性と抗がん活動に対する電子提供群と電子除去群の影響を調査する.
- 化学療法研究のさらなる発展のための有望な候補者を特定する.
主な方法:
- 6つのルテニウム複合体 (1-6) の合成と特徴付け
- 充電,色,リガンドの酸化状態を含む物理化学的性質の調査.
- 癌細胞系と細胞吸収メカニズムに対する in vitro 細胞毒性の評価
主要な成果:
- コンプレックス1−4 (電子提供群) は陽性電荷があり,深赤色であり,中性,青色/紫色コンプレックス5−6 (電子除去群) よりも著しく高い細胞毒性 (IC50=0. 07- 0. 7μM) を示した.
- 複合体1は,受動的輸送と様々な細胞部位 (核,リソソーム,ミトコンドリア,細胞質) で適度な蓄積を通じて効率的な細胞吸収を示した.
- 複合体1はDNAと直接相互作用し,ミトコンドリア機能が低下し,複数の作用形態を示した.
結論:
- カテコラートリガンド (EDG vs EWG) の性質は,ルテニウム複合体の物理化学的および生物学的性質に大きな影響を与える.
- コンプレックス1は,強力な細胞毒性,多標的作用,そして有利な細胞吸収により,非常に有望な抗がん剤候補である.
- 予備的な生物分布研究は,複合体1が化学療法研究におけるさらなる in vivo 評価に適していることを示唆している.
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