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Ruthenium-arene complexes with NSAIDs: Synthesis, characterization and bioactivity

Abstract

Two non-steroidal antiinflammatory drugs, indomethacin and mefenamic acid, were coordinated to Ru(II)-arenes to give four new complexes. The cytotoxic activity of the ligands and ruthenium complexes was tested in three human cancer cell lines (K562, A549, MDA-MB-231) and non-tumour human fetal lung fibroblast cells (MRC-5), by MTT assay. Cytotoxicity studies revealed that indomethacin Ru(II)-arene complexes, 1 and 3, displayed good cytotoxicity and an apparent cytoselective profile. The IC50 values obtained in leukemia K562 cells, were comparable to cisplatin (10.3 µM (CDDP), 11.9 µM (1) and 13.2 µM (3)). Flow cytometric analysis of 1 and 3, in triple-negative breast cancer MDA-MB-231 cells revealed interesting mechanism of action. At IC50 concentrations, 1 and 3 arrested cell cycle progression in the S phase and caused rapid accumulation of cells in sub-G1 (up to 48 %), while Annexin V-FITC/PI staining showed simultaneous occurrence of apoptotic and necrotic cell population, at approximately similar levels of 20%. Measurement of reactive oxygen species (ROS) production, by DCFH-DA staining, confirmed potential of 1 and 3 to increase ROS even more than cisplatin. The interaction of the complexes with serum albumins showed their potential ability to bind tightly and reversibly to the albumins. The affinity of the complexes with calf-thymus DNA was investigated by UV-vis spectroscopy, viscosity measurements and fluorescence emission spectroscopy for the competitive studies of the complexes with ethidium bromide revealing their interaction probably via intercalation. Altogether results strongly suggested the potential of complexes 1 and 3, to alter cell cycle progression and cause DNA-damage by means of direct DNA-binding or indirectly, by ROS production.

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Publication details

The article was received on 13 Nov 2017, accepted on 10 Jan 2018 and first published on 11 Jan 2018


Article type: Paper
DOI: 10.1039/C7NJ04416J
Citation: New J. Chem., 2018, Accepted Manuscript
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    Ruthenium-arene complexes with NSAIDs: Synthesis, characterization and bioactivity

    A. Tadić, J. Poljarević, M. P. Krstić, M. Kajzerberger, S. Aranđelović, S. Radulović, C. Kakoulidou, A. Papadopoulos, G. L. Psomas and S. Grguric-Sipka, New J. Chem., 2018, Accepted Manuscript , DOI: 10.1039/C7NJ04416J

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