Structure-Activity Relationships of Targeted Ru-II(eta(6)-p-Cymene) Anticancer Complexes with Flavonol-Derived Ligands

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(eta(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 Ha 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-activity 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(eta(6)-p-cymene) complexes are more potent antiproliferative agents, which can be explained by potential multitargeted properties.