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 [(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 ).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.
Filak
Lukas K
LK
Institute of Inorganic Chemistry, University of Vienna, Währinger Strasse 42, 1090, Vienna, Austria.
Mühlgassner
Gerhard
G
Jakupec
Michael A
MA
Heffeter
Petra
P
Berger
Walter
W
Arion
Vladimir B
VB
Keppler
Bernhard K
BK
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004247:DNA / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D008024:Ligands; D009942:Organometallic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011804:Quinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013057:Spectrum Analysis
D000970:Antineoplastic Agents; D001552:Benzazepines; D007364:Intercalating Agents; D008024:Ligands; D009942:Organometallic Compounds; D011804:Quinolines; D004247:DNA; C037219:quinoline; D018844:Cyclin-Dependent Kinases