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

Abstract
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.
AuthorsLukas K Filak, Gerhard Mühlgassner, Michael A Jakupec, Petra Heffeter, Walter Berger, Vladimir B Arion, Bernhard K Keppler
JournalJournal of biological inorganic chemistry : JBIC : a publication of the Society of Biological Inorganic Chemistry (J Biol Inorg Chem) Vol. 15 Issue 6 Pg. 903-18 (Aug 2010) ISSN: 1432-1327 [Electronic] Germany
PMID20369265 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Antineoplastic Agents
  • Benzazepines
  • Intercalating Agents
  • Ligands
  • Organometallic Compounds
  • Quinolines
  • DNA
  • quinoline
  • Cyclin-Dependent Kinases
Topics
  • Animals
  • Antineoplastic Agents (chemical synthesis, chemistry, metabolism, pharmacology)
  • Benzazepines (chemical synthesis, chemistry, metabolism, pharmacology)
  • Cell Cycle (drug effects)
  • Cell Line, Tumor
  • Crystallography, X-Ray
  • Cyclin-Dependent Kinases (antagonists & inhibitors)
  • DNA (metabolism)
  • Humans
  • Inhibitory Concentration 50
  • Intercalating Agents (chemical synthesis, chemistry, metabolism, pharmacology)
  • Ligands
  • Organometallic Compounds (chemical synthesis, chemistry, metabolism, pharmacology)
  • Quinolines (chemical synthesis, chemistry, metabolism, pharmacology)
  • Spectrum Analysis

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