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

Filak LK, Mühlgassner G, Jakupec MA, Heffeter P, Berger W, Arion VB, Keppler BK - J. Biol. Inorg. Chem. (2010)

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Inorganic Chemistry, University of Vienna, Währinger Strasse 42, 1090, Vienna, Austria.

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.

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Concentration-dependent inhibition of cdk1/cyclin B activity (mean ± standard deviations) by indoloquinoline L2, indolobenzazepine derivative L4, and the corresponding osmium complexes 7 and 11, in vitro. Flavopiridol (FP) was used as a positive control
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Fig10: Concentration-dependent inhibition of cdk1/cyclin B activity (mean ± standard deviations) by indoloquinoline L2, indolobenzazepine derivative L4, and the corresponding osmium complexes 7 and 11, in vitro. Flavopiridol (FP) was used as a positive control

Mentions: Measurements of kinase activity of recombinant cdk/cyclin complexes after exposure to indoloquinoline L2, indolobenzazepine derivative L4, and the corresponding osmium complexes 7 and 11 were performed in the presence of (γ-32P)ATP and histone H1 as the substrate for phosphorylation. Generally, the activity of cdk2/cyclin E was affected by the test compounds (including the cdk inhibitor flavopiridol, which was used as a reference) to a higher degree than that of cdk1/cyclin B, except for 11, which inhibits both kinases to nearly equal extent. Whereas the IC50 value for cdk1/cyclin B inhibition was only reached within the concentration range up to 100 μM in the case of 11 (90 μM), those for cdk2/cyclin E inhibition decrease in the following rank order: 11 (100 μM) > L4 (73 μM) > L2 (70 μM) > 7 (13 μM). Thus, the inhibitory potency of L2 resembles that of L4, despite the 2 orders of magnitude higher cytotoxicity, strongly suggesting that other molecular effects account for the increased cytotoxicity. Complexation with osmium has different consequences for kinase inhibition. Whereas complex 7 inhibits cdk2/cyclin E to a somewhat higher degree than uncomplexed indoloquinoline L2, comparison of complex 11 with indolobenzazepine derivative L4 reveals an increased inhibitory activity in cdk1/cyclin B only (Figs. 9, 10).Fig. 9


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

Filak LK, Mühlgassner G, Jakupec MA, Heffeter P, Berger W, Arion VB, Keppler BK - J. Biol. Inorg. Chem. (2010)

Concentration-dependent inhibition of cdk1/cyclin B activity (mean ± standard deviations) by indoloquinoline L2, indolobenzazepine derivative L4, and the corresponding osmium complexes 7 and 11, in vitro. Flavopiridol (FP) was used as a positive control
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2908761&req=5

Fig10: Concentration-dependent inhibition of cdk1/cyclin B activity (mean ± standard deviations) by indoloquinoline L2, indolobenzazepine derivative L4, and the corresponding osmium complexes 7 and 11, in vitro. Flavopiridol (FP) was used as a positive control
Mentions: Measurements of kinase activity of recombinant cdk/cyclin complexes after exposure to indoloquinoline L2, indolobenzazepine derivative L4, and the corresponding osmium complexes 7 and 11 were performed in the presence of (γ-32P)ATP and histone H1 as the substrate for phosphorylation. Generally, the activity of cdk2/cyclin E was affected by the test compounds (including the cdk inhibitor flavopiridol, which was used as a reference) to a higher degree than that of cdk1/cyclin B, except for 11, which inhibits both kinases to nearly equal extent. Whereas the IC50 value for cdk1/cyclin B inhibition was only reached within the concentration range up to 100 μM in the case of 11 (90 μM), those for cdk2/cyclin E inhibition decrease in the following rank order: 11 (100 μM) > L4 (73 μM) > L2 (70 μM) > 7 (13 μM). Thus, the inhibitory potency of L2 resembles that of L4, despite the 2 orders of magnitude higher cytotoxicity, strongly suggesting that other molecular effects account for the increased cytotoxicity. Complexation with osmium has different consequences for kinase inhibition. Whereas complex 7 inhibits cdk2/cyclin E to a somewhat higher degree than uncomplexed indoloquinoline L2, comparison of complex 11 with indolobenzazepine derivative L4 reveals an increased inhibitory activity in cdk1/cyclin B only (Figs. 9, 10).Fig. 9

Bottom Line: 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 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.

View Article: PubMed Central - PubMed

Affiliation: Institute of Inorganic Chemistry, University of Vienna, Währinger Strasse 42, 1090, Vienna, Austria.

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.

Show MeSH
Related in: MedlinePlus