期刊
JOURNAL OF BIOLOGICAL INORGANIC CHEMISTRY
卷 15, 期 6, 页码 903-918出版社
SPRINGER
DOI: 10.1007/s00775-010-0653-y
关键词
Indolo[3,2-d]benzazepines; Indolo[3,2-c]quinolines; Osmium; Ruthenium
资金
- FWF [P20897, P22339]
- Austrian Science Fund (FWF) [P 22339, P 20897] Funding Source: researchfish
- Austrian Science Fund (FWF) [P20897, P22339] Funding Source: Austrian Science Fund (FWF)
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 [(eta(6)-p-cymene)M(II)(L (1) )Cl]Cl, where M is Ru (4) and Os (6), [(eta(6)-p-cymene)M(II)(L (2) )Cl]Cl, where M is Ru (5) and Os (7), [(eta(6)-p-cymene)M(II)(L (3) )Cl]Cl, where M is Ru (8) and Os (10), and [(eta(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) center dot HCl, 4 center dot H(2)O, 5, and 9 center dot 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.
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