Organometallic indolo[3,2-c]quinolines versus indolo[3,2-d]benzazepines: synthesis, structural and spectroscopic characterization, and biological efficacy

The synthesis of ruthenium(II) and osmium(II) arene complexes with the closely related indolo[3,2-c]quinolines N-(11H-indolo[3,2-c]quinolin-6-yl)-ethane-1,2-diamine (L (1)) and N′-(11H-indolo[3,2-c]quinolin-6-yl)-N,N-dimethylethane-1,2-diamine (L (2)) and indolo[3,2-d]benzazepines N-(7,12-dihydroindolo-[3,2-d][1]benzazepin-6-yl)-ethane-1,2-diamine (L (3)) and N′-(7,12-dihydroindolo-[3,2-d][1]benzazepin-6-yl)-N,N-dimethylethane-1,2-diamine (L (4)) of the general formulas [(η(6)-p-cymene)M(II)(L (1))Cl]Cl, where M is Ru (4) and Os (6), [(η(6)-p-cymene)M(II)(L (2))Cl]Cl, where M is Ru (5) and Os (7), [(η(6)-p-cymene)M(II)(L (3))Cl]Cl, where M is Ru (8) and Os (10), and [(η(6)-p-cymene)M(II)(L (4))Cl]Cl, where M is Ru (9) and Os (11), is reported. The compounds have been comprehensively characterized by elemental analysis, electrospray ionization mass spectrometry, spectroscopy (IR, UV–vis, and NMR), and X-ray crystallography (L (1)·HCl, 4·H(2)O, 5, and 9·2.5H(2)O). Structure–activity relationships with regard to cytotoxicity and cell cycle effects in human cancer cells as well as cyclin-dependent kinase (cdk) inhibition and DNA intercalation in cell-free settings have been established. The metal-free indolo[3,2-c]quinolines inhibit cancer cell growth in vitro, with IC(50) values in the high nanomolar range, whereas those of the related indolo[3,2-d]benzazepines are in the low micromolar range. In cell-free experiments, these classes of compounds inhibit the activity of cdk2/cyclin E, but the much higher cytotoxicity and stronger cell cycle effects of indoloquinolines L (1) and 7 are not paralleled by a substantially higher kinase inhibition compared with indolobenzazepines L (4) and 11, arguing for additional targets and molecular effects, such as intercalation into DNA. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s00775-010-0653-y) contains supplementary material, which is available to authorized users.