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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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Mentions: Indolo-[3,2-c]quinolines 1a and 1b, combining both structural units, namely quinolin-2(1H)-one and indole, are now available [11–13], and further derivatization enables chemical diversification of this class of fused heteroaromatics [14–17]. The compounds shown in Structure 2 were tested for cytotoxicity at the US National Cancer Institute in a panel of about 60 human cancer cell lines. The results of this screening showed that 1a and 1b exhibit respectable inhibitory activity, with mean 50% cell growth inhibition concentrations (GI50) of 19.0 and 18.2 μM, respectively. Substitution at the lactam unit led to enhanced cytotoxicity (2a, 4.26 μM vs. 1a, 19.0 μM), which was further increased by converting the keto function in 2a and 2b into an oxime group, yielding 3a and 3b (GI50 values of 1.70 and 1.35 μM, respectively) [16].Structure 2


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)

 
© Copyright Policy
Related In: Results  -  Collection

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

Str2:  
Mentions: Indolo-[3,2-c]quinolines 1a and 1b, combining both structural units, namely quinolin-2(1H)-one and indole, are now available [11–13], and further derivatization enables chemical diversification of this class of fused heteroaromatics [14–17]. The compounds shown in Structure 2 were tested for cytotoxicity at the US National Cancer Institute in a panel of about 60 human cancer cell lines. The results of this screening showed that 1a and 1b exhibit respectable inhibitory activity, with mean 50% cell growth inhibition concentrations (GI50) of 19.0 and 18.2 μM, respectively. Substitution at the lactam unit led to enhanced cytotoxicity (2a, 4.26 μM vs. 1a, 19.0 μM), which was further increased by converting the keto function in 2a and 2b into an oxime group, yielding 3a and 3b (GI50 values of 1.70 and 1.35 μM, respectively) [16].Structure 2

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