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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–effect curves of indolobenzazepine derivative L4 in comparison with ruthenium complexes 8 and 9 and osmium complexes 10 and 11 in the human cancer cell lines A549 (a), SW480 (b), and CH1 (c), as obtained by the MTT assay (continuous exposure for 96 h)
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Fig6: Concentration–effect curves of indolobenzazepine derivative L4 in comparison with ruthenium complexes 8 and 9 and osmium complexes 10 and 11 in the human cancer cell lines A549 (a), SW480 (b), and CH1 (c), as obtained by the MTT assay (continuous exposure for 96 h)

Mentions: The cytotoxicity of compounds L2, L4, and 5–11 was assessed by means of a colorimetric microculture assay (MTT assay) in three human cancer cell lines, namely, CH1 (ovarian carcinoma), SW480 (colon adenocarcinoma), and A549 (non-small-cell lung carcinoma). The sensitivities of these cell lines show mostly small differences, but the generally more chemoresistant non-small-cell lung cancer cell line A549 is also the least sensitive throughout this series of compounds. The generally more chemosensitive ovarian cancer cell line CH1 is the most sensitive only to indolobenzazepine derivatives L4 and 8–11, whereas indoloquinoline derivatives L2 and 5–7 are most cytotoxic to the colon cancer cell line SW480. The calculated IC50 values are listed in Table 3, and the corresponding concentration–effect curves are depicted in Figs. 5, 6, and 7, illustrating the following structure–activity relationships: the high cytotoxic potency of indoloquinoline derivative L2 could only be slightly (if at all) increased by complexation, with hardly a difference between ruthenium and osmium (up to 1.8 times in the case of ruthenium complex 5 and up to 1.6 times in the case of osmium complex 7, based on a comparison of IC50 values), which might result from insufficient stability in the cell culture medium. In any case, there are no clear-cut synergistic effects of metal and ligand. The cytotoxicity of complex 6 differs only slightly from that of analogue 7, showing that terminal dimethylation of the ethane-1,2-diamine side chain has little consequence for biological activity (Fig. 5).Table 3


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–effect curves of indolobenzazepine derivative L4 in comparison with ruthenium complexes 8 and 9 and osmium complexes 10 and 11 in the human cancer cell lines A549 (a), SW480 (b), and CH1 (c), as obtained by the MTT assay (continuous exposure for 96 h)
© Copyright Policy
Related In: Results  -  Collection

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

Fig6: Concentration–effect curves of indolobenzazepine derivative L4 in comparison with ruthenium complexes 8 and 9 and osmium complexes 10 and 11 in the human cancer cell lines A549 (a), SW480 (b), and CH1 (c), as obtained by the MTT assay (continuous exposure for 96 h)
Mentions: The cytotoxicity of compounds L2, L4, and 5–11 was assessed by means of a colorimetric microculture assay (MTT assay) in three human cancer cell lines, namely, CH1 (ovarian carcinoma), SW480 (colon adenocarcinoma), and A549 (non-small-cell lung carcinoma). The sensitivities of these cell lines show mostly small differences, but the generally more chemoresistant non-small-cell lung cancer cell line A549 is also the least sensitive throughout this series of compounds. The generally more chemosensitive ovarian cancer cell line CH1 is the most sensitive only to indolobenzazepine derivatives L4 and 8–11, whereas indoloquinoline derivatives L2 and 5–7 are most cytotoxic to the colon cancer cell line SW480. The calculated IC50 values are listed in Table 3, and the corresponding concentration–effect curves are depicted in Figs. 5, 6, and 7, illustrating the following structure–activity relationships: the high cytotoxic potency of indoloquinoline derivative L2 could only be slightly (if at all) increased by complexation, with hardly a difference between ruthenium and osmium (up to 1.8 times in the case of ruthenium complex 5 and up to 1.6 times in the case of osmium complex 7, based on a comparison of IC50 values), which might result from insufficient stability in the cell culture medium. In any case, there are no clear-cut synergistic effects of metal and ligand. The cytotoxicity of complex 6 differs only slightly from that of analogue 7, showing that terminal dimethylation of the ethane-1,2-diamine side chain has little consequence for biological activity (Fig. 5).Table 3

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