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

摘要

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 (L3) 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 (L) 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-pcymene)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 ~1HCl, 4H _2O, 5, and 9-2.5H _2O). 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.