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.