Structure鈥揂ctivity Relationships of Targeted RuII(畏6-p-Cymene) Anticancer Complexes with Flavonol-Derived Ligands

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• 作者：Andrea Kurzwernhart ; Wolfgang Kandioller ; Simone B盲chler ; Caroline Bartel ; Sanela Martic ; Magdalena Buczkowska ; Gerhard M眉hlgassner ; Michael A. Jakupec ; Heinz-Bernhard Kraatz ; Patrick J. Bednarski ; Vladimir B. Arion ; Doris Marko ; Bernhard K. Keppler ; Christian G. Hartinger
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：December 13, 2012
• 年：2012
• 卷：55
• 期：23
• 页码：10512-10522
• 全文大小：414K
• 年卷期：v.55,no.23(December 13, 2012)
• ISSN：1520-4804

文摘

Ru^II(arene) complexes have been shown to be promising anticancer agents, capable of overcoming major drawbacks of currently used chemotherapeutics. We have synthesized Ru^II(畏⁶-arene) compounds carrying bioactive flavonol ligands with the aim to obtain multitargeted anticancer agents. To validate this concept, studies on the mode of action of the complexes were conducted which indicated that they form covalent bonds to DNA, have only minor impact on the cell cycle, but inhibit CDK2 and topoisomerase II伪 in vitro. The cytotoxic activity was determined in human cancer cell lines, resulting in very low IC₅₀ values as compared to other Ru^II(arene) complexes and showing a structure鈥揳ctivity relationship dependent on the substitution pattern of the flavonol ligand. Furthermore, the inhibition of cell growth correlates well with the topoisomerase inhibitory activity. Compared to the flavonol ligands, the Ru^II(畏⁶-p-cymene) complexes are more potent antiproliferative agents, which can be explained by potential multitargeted properties.