Ruthenium-arene complexes with NSAIDs: synthesis, characterization and bioactivity
2018
Authors
Tadić, AnaPoljarević, Jelena
Krstić, Milena
Kajzerberger, Marijana
Aranđelović, Sandra
Radulović, Siniša
Kakoulidou, Chrisoula
Papadopoulos, Athanasios N.
Psomas, George
Grgurić-Šipka, Sanja
Article (Published version)
Metadata
Show full item recordAbstract
Two non-steroidal antiinflammatory drugs indomethacin and mefenamic acid were coordinated to Ru(II)-arenes to afford four new complexes. The cytotoxic activities of the ligands and ruthenium complexes were 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 apparent cytoselective profiles. The IC50 values obtained in leukemia K562 cells were comparable to those of cisplatin (10.3 mu M (CDDP), 11.9 mu M (1) and 13.2 mu M (3)). Flow cytometric analysis of 1 and 3 in triple-negative breast cancer MDA-MB-231 cells revealed an interesting mechanism of action. At IC50 concentrations, 1 and 3 arrested cell cycle progression in S phase and caused rapid accumulation of cells in sub-G1 phase (up to 48%), while Annexin V-FITC/PI staining showed simultaneous occurrence of apoptotic and necrotic cell popula...tions at approximately similar levels of 20%. Measurement of reactive oxygen species (ROS) production by DCFH-DA staining confirmed the 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 albumins. The affinity of the complexes to calf-thymus DNA was investigated by UV-vis spectroscopy, viscosity measurements and fluorescence emission spectroscopy for competitive studies of the complexes with ethidium bromide, revealing that their interaction probably occurs via intercalation. Taken together, the results strongly suggest 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.
Keywords:
NONSTEROIDAL ANTIINFLAMMATORY DRUGS / MEFENAMIC-ACID / BIOLOGICAL EVALUATION / IN-VITRO / CRYSTAL-STRUCTURE / ZINC-COMPLEXES / DNA-BINDING / COPPER(II) COMPLEXES / NICKEL(II) COMPLEXES / ANTIOXIDANT ACTIVITYSource:
New Journal of Chemistry, 2018, 42, 4, 3001-3019Publisher:
- Royal Soc Chemistry, Cambridge
Funding / projects:
- Pharmacodynamic and pharmacogenomic research of new drugs in the treatment of solid tumors (RS-MESTD-Integrated and Interdisciplinary Research (IIR or III)-41026)
- Rational design and synthesis of biologically active and coordination compounds and functional materials, relevant for (bio)nanotechnology (RS-MESTD-Basic Research (BR or ON)-172035)
- Hellenic Foundation for Research and Innovation (HFRI), Greek Ministry of Education, Research and Religion
- General Secretariat for Research and Technology (GSRT)
Note:
- Supplementary material: http://cherry.chem.bg.ac.rs/handle/123456789/3038
DOI: 10.1039/c7nj04416j
ISSN: 1144-0546
WoS: 000424970300077
Scopus: 2-s2.0-85042029085
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Institution/Community
Hemijski fakultet / Faculty of ChemistryTY - JOUR AU - Tadić, Ana AU - Poljarević, Jelena AU - Krstić, Milena AU - Kajzerberger, Marijana AU - Aranđelović, Sandra AU - Radulović, Siniša AU - Kakoulidou, Chrisoula AU - Papadopoulos, Athanasios N. AU - Psomas, George AU - Grgurić-Šipka, Sanja PY - 2018 UR - https://cherry.chem.bg.ac.rs/handle/123456789/2093 AB - Two non-steroidal antiinflammatory drugs indomethacin and mefenamic acid were coordinated to Ru(II)-arenes to afford four new complexes. The cytotoxic activities of the ligands and ruthenium complexes were 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 apparent cytoselective profiles. The IC50 values obtained in leukemia K562 cells were comparable to those of cisplatin (10.3 mu M (CDDP), 11.9 mu M (1) and 13.2 mu M (3)). Flow cytometric analysis of 1 and 3 in triple-negative breast cancer MDA-MB-231 cells revealed an interesting mechanism of action. At IC50 concentrations, 1 and 3 arrested cell cycle progression in S phase and caused rapid accumulation of cells in sub-G1 phase (up to 48%), while Annexin V-FITC/PI staining showed simultaneous occurrence of apoptotic and necrotic cell populations at approximately similar levels of 20%. Measurement of reactive oxygen species (ROS) production by DCFH-DA staining confirmed the 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 albumins. The affinity of the complexes to calf-thymus DNA was investigated by UV-vis spectroscopy, viscosity measurements and fluorescence emission spectroscopy for competitive studies of the complexes with ethidium bromide, revealing that their interaction probably occurs via intercalation. Taken together, the results strongly suggest 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. PB - Royal Soc Chemistry, Cambridge T2 - New Journal of Chemistry T1 - Ruthenium-arene complexes with NSAIDs: synthesis, characterization and bioactivity VL - 42 IS - 4 SP - 3001 EP - 3019 DO - 10.1039/c7nj04416j ER -
@article{ author = "Tadić, Ana and Poljarević, Jelena and Krstić, Milena and Kajzerberger, Marijana and Aranđelović, Sandra and Radulović, Siniša and Kakoulidou, Chrisoula and Papadopoulos, Athanasios N. and Psomas, George and Grgurić-Šipka, Sanja", year = "2018", abstract = "Two non-steroidal antiinflammatory drugs indomethacin and mefenamic acid were coordinated to Ru(II)-arenes to afford four new complexes. The cytotoxic activities of the ligands and ruthenium complexes were 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 apparent cytoselective profiles. The IC50 values obtained in leukemia K562 cells were comparable to those of cisplatin (10.3 mu M (CDDP), 11.9 mu M (1) and 13.2 mu M (3)). Flow cytometric analysis of 1 and 3 in triple-negative breast cancer MDA-MB-231 cells revealed an interesting mechanism of action. At IC50 concentrations, 1 and 3 arrested cell cycle progression in S phase and caused rapid accumulation of cells in sub-G1 phase (up to 48%), while Annexin V-FITC/PI staining showed simultaneous occurrence of apoptotic and necrotic cell populations at approximately similar levels of 20%. Measurement of reactive oxygen species (ROS) production by DCFH-DA staining confirmed the 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 albumins. The affinity of the complexes to calf-thymus DNA was investigated by UV-vis spectroscopy, viscosity measurements and fluorescence emission spectroscopy for competitive studies of the complexes with ethidium bromide, revealing that their interaction probably occurs via intercalation. Taken together, the results strongly suggest 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.", publisher = "Royal Soc Chemistry, Cambridge", journal = "New Journal of Chemistry", title = "Ruthenium-arene complexes with NSAIDs: synthesis, characterization and bioactivity", volume = "42", number = "4", pages = "3001-3019", doi = "10.1039/c7nj04416j" }
Tadić, A., Poljarević, J., Krstić, M., Kajzerberger, M., Aranđelović, S., Radulović, S., Kakoulidou, C., Papadopoulos, A. N., Psomas, G.,& Grgurić-Šipka, S.. (2018). Ruthenium-arene complexes with NSAIDs: synthesis, characterization and bioactivity. in New Journal of Chemistry Royal Soc Chemistry, Cambridge., 42(4), 3001-3019. https://doi.org/10.1039/c7nj04416j
Tadić A, Poljarević J, Krstić M, Kajzerberger M, Aranđelović S, Radulović S, Kakoulidou C, Papadopoulos AN, Psomas G, Grgurić-Šipka S. Ruthenium-arene complexes with NSAIDs: synthesis, characterization and bioactivity. in New Journal of Chemistry. 2018;42(4):3001-3019. doi:10.1039/c7nj04416j .
Tadić, Ana, Poljarević, Jelena, Krstić, Milena, Kajzerberger, Marijana, Aranđelović, Sandra, Radulović, Siniša, Kakoulidou, Chrisoula, Papadopoulos, Athanasios N., Psomas, George, Grgurić-Šipka, Sanja, "Ruthenium-arene complexes with NSAIDs: synthesis, characterization and bioactivity" in New Journal of Chemistry, 42, no. 4 (2018):3001-3019, https://doi.org/10.1039/c7nj04416j . .