title: Biological activity of ruthenium and osmium arene complexes with modified paullones in human cancer cells.
abstract: In an attempt to combine the ability of indolobenzazepines (paullones) to inhibit cyclin-dependent kinases (Cdks) and that of platinum-group metal ions to interact with proteins and DNA, ruthenium(II) and osmium(II) arene complexes with paullones were prepared, expecting synergies and an increase of solubility of paullones. Complexes with the general formula [M(II)Cl(η(6)-p-cymene)L]Cl, where M=Ru (1, 3) or Os (2, 4), and L=L(1) (1, 2) or L(2) (3, 4), L(1)=N-(9-bromo-7,12-dihydroindolo[3,2-d][1]-benzazepin-6(5H)-yliden-N'-(2-hydroxybenzylidene)azine and L(2)=N-(9-bromo-7,12-dihydroindolo[3,2-d][1]benzazepin-6-yl)-N'-[3-hydroxy-5-(hydroxymethyl)-2-methylpyridin-4-yl-methylene]azinium chloride (L(2)(*)HCl), were now investigated regarding cytotoxicity and accumulation in cancer cells, impact on the cell cycle, capacity of inhibiting DNA synthesis and inducing apoptosis as well as their ability to inhibit Cdk activity. The MTT (3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide) assay yielded IC(50) values in the nanomolar to low micromolar range. In accordance with cytotoxicity data, the BrdU assay showed that 1 is the most and 4 the least effective of these compounds regarding inhibition of DNA synthesis. Effects on the cell cycle are minor, although concentration-dependent inhibition of Cdk2/cyclin E activity was observed in cell-free experiments. Induction of apoptosis is most pronounced for complex 1, accompanied by a low fraction of necrotic cells, as observed by annexin V-fluorescein isothiocyanate/propidium iodide staining and flow cytometric analysis.
authors.affiliation: University of Vienna, Institute of Inorganic Chemistry, Währinger Straße 42, A-1090 Vienna, Austria.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Mühlgassner
authors.forename: Caroline
authors.initials: C
authors.lastname: Bartel
authors.forename: Wolfgang F
authors.initials: WF
authors.lastname: Schmid
authors.forename: Michael A
authors.initials: MA
authors.lastname: Jakupec
authors.forename: Vladimir B
authors.initials: VB
authors.lastname: Arion
authors.forename: Bernhard K
authors.initials: BK
authors.lastname: Keppler
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001552:Benzazepines / Q000737:chemistry*; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology; D006801:Humans; D017892:Osmium Compounds / Q000737:chemistry / Q000494:pharmacology*; D017975:Ruthenium Compounds / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001552:Benzazepines; D017892:Osmium Compounds; D017975:Ruthenium Compounds; C547599:paullone