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Synthesis, characterization and biological evaluation of novel Ru(II)–arene complexes containing intercalating ligands


Nikolić, Stefan; Rangasamy, Loganathan; Gligorijević, Nevenka; Aranđelović, Sandra; Radulović, Siniša; Gasser, Gilles; Grgurić-Šipka, Sanja (2016). Synthesis, characterization and biological evaluation of novel Ru(II)–arene complexes containing intercalating ligands. Journal of Inorganic Biochemistry, 160:156-165.

Abstract

Three new ruthenium(II)–arene complexes, namely [(η6-p-cymene)Ru(Me2dppz)Cl]PF6 (1), [(η6-benzene)Ru(Me2dppz)Cl]PF6 (2) and [(η6-p-cymene)Ru(aip)Cl]PF6 (3) (Me2dppz = 11,12-dimethyldipyrido[3,2-a:2′,3′-c]phenazine; aip = 2-(9-anthryl)-1H-imidazo[4,5-f] [1,10] phenanthroline) have been synthesized and characterized using different spectroscopic techniques including elemental analysis. The complexes were found to be well soluble and stable in DMSO. The biological activity of the three complexes was tested in three different human cancer cell lines (A549, MDA-MB-231 and HeLa) and in one human non-cancerous cell line (MRC-5). Complexes 1 and 3, carrying η6-p-cymene as the arene ligand, were shown to be toxic in all cell lines in the low micromolar/subnanomolar range, with complex 1 being the most cytotoxic complex of the series. Flow cytometry analysis revealed that complex 1 caused concentration- and time-dependent arrest of the cell cycle in G2-M and S phases in HeLa cells. This event is followed by the accumulation of the sub-G1 DNA content after 48 h, in levels higher than cisplatin and in the absence of phosphatidylserine externalization. Fluorescent microscopy and acridine orange/ethidium bromide staining revealed that complex 1 induced both apoptotic and necrotic cell morphology characteristics. Drug-accumulation and DNA-binding studies performed by inductively coupled plasma mass spectrometry in HeLa cells showed that the total ruthenium uptake increased in a time- and concentration-dependent manner, and that complex 1 accumulated more efficiently than cisplatin at equimolar concentrations. The introduction of a Me2dppz ligand into the ruthenium(II)-p-cymene scaffold was found to allow the discovery of a strongly cytotoxic complex with significantly higher cellular uptake and DNA-binding properties than cisplatin.

Abstract

Three new ruthenium(II)–arene complexes, namely [(η6-p-cymene)Ru(Me2dppz)Cl]PF6 (1), [(η6-benzene)Ru(Me2dppz)Cl]PF6 (2) and [(η6-p-cymene)Ru(aip)Cl]PF6 (3) (Me2dppz = 11,12-dimethyldipyrido[3,2-a:2′,3′-c]phenazine; aip = 2-(9-anthryl)-1H-imidazo[4,5-f] [1,10] phenanthroline) have been synthesized and characterized using different spectroscopic techniques including elemental analysis. The complexes were found to be well soluble and stable in DMSO. The biological activity of the three complexes was tested in three different human cancer cell lines (A549, MDA-MB-231 and HeLa) and in one human non-cancerous cell line (MRC-5). Complexes 1 and 3, carrying η6-p-cymene as the arene ligand, were shown to be toxic in all cell lines in the low micromolar/subnanomolar range, with complex 1 being the most cytotoxic complex of the series. Flow cytometry analysis revealed that complex 1 caused concentration- and time-dependent arrest of the cell cycle in G2-M and S phases in HeLa cells. This event is followed by the accumulation of the sub-G1 DNA content after 48 h, in levels higher than cisplatin and in the absence of phosphatidylserine externalization. Fluorescent microscopy and acridine orange/ethidium bromide staining revealed that complex 1 induced both apoptotic and necrotic cell morphology characteristics. Drug-accumulation and DNA-binding studies performed by inductively coupled plasma mass spectrometry in HeLa cells showed that the total ruthenium uptake increased in a time- and concentration-dependent manner, and that complex 1 accumulated more efficiently than cisplatin at equimolar concentrations. The introduction of a Me2dppz ligand into the ruthenium(II)-p-cymene scaffold was found to allow the discovery of a strongly cytotoxic complex with significantly higher cellular uptake and DNA-binding properties than cisplatin.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Department of Chemistry
Dewey Decimal Classification:540 Chemistry
Language:English
Date:2016
Deposited On:09 Feb 2017 14:00
Last Modified:09 Feb 2017 14:01
Publisher:Elsevier
ISSN:0162-0134
Publisher DOI:https://doi.org/10.1016/j.jinorgbio.2016.01.005

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