title: Structure-activity relationships of targeted RuII(η6-p-cymene) anticancer complexes with flavonol-derived ligands.
abstract: RuII(arene) complexes have been shown to be promising anticancer agents, capable of overcoming major drawbacks of currently used chemotherapeutics. We have synthesized RuII(η6-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 IIα in vitro. The cytotoxic activity was determined in human cancer cell lines, resulting in very low IC50 values as compared to other RuII(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 RuII(η6-p-cymene) complexes are more potent antiproliferative agents, which can be explained by potential multitargeted properties.
authors.affiliation: Institute of Inorganic Chemistry, University of Vienna, Waehringer Strasse 42, 1090 Vienna, Austria.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kurzwernhart
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Kandioller
authors.forename: Simone
authors.initials: S
authors.lastname: Bächler
authors.forename: Caroline
authors.initials: C
authors.lastname: Bartel
authors.forename: Sanela
authors.initials: S
authors.lastname: Martic
authors.forename: Magdalena
authors.initials: M
authors.lastname: Buczkowska
authors.forename: Gerhard
authors.initials: G
authors.lastname: Mühlgassner
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jakupec
authors.forename: Heinz-Bernhard
authors.initials: HB
authors.lastname: Kraatz
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Bednarski
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Arion
authors.forename: Doris
authors.initials: D
authors.lastname: Marko
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
authors.forename: Christian G
authors.initials: CG
authors.lastname: Hartinger
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors; D004250:DNA Topoisomerases, Type II / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D044948:Flavonols / Q000737:chemistry*; D006801:Humans; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D017975:Ruthenium Compounds / Q000737:chemistry* / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D044948:Flavonols; D008024:Ligands; D017975:Ruthenium Compounds; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D004250:DNA Topoisomerases, Type II