Organometallic indolo32-cquinolines versus indolo32-dbenzazepines: 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 (>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 [(η⁶-p-cymene)M^II(>L^>1)Cl]Cl, where M is Ru (>4) and Os (>6), [(η⁶-p-cymene)M^II(>L^>2)Cl]Cl, where M is Ru (>5) and Os (>7), [(η⁶-p-cymene)M^II(>L^>3)Cl]Cl, where M is Ru (>8) and Os (>10), and [(η⁶-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·H2O, >5, and >9·2.5H2O). 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 IC50 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 materialThe online version of this article (doi:10.1007/s00775-010-0653-y) contains supplementary material, which is available to authorized users.