Since the discovery of the biological activity of cisplatin, much effort has been devoted to search for other effective metallodrugs that may avoid certain problems associated to cisplatin, such as high toxicity or severe side effects. Ru (II) organometallic compounds are emerging as promising new therapeutic drugs. Cationic Ru (II) arene complexes have shown to display high antitumour activity both in vitro and in vivo. In this context, recently a new family of arene Ru (II) complexes bearing a diaminotriazine derivative have been synthesized and characterized. The DNA interaction and biological activity of one of these complexes, [RuCl(p-cymene)(қ2-N,N-2-pydaT)]BF4 denoted as Ru-Cl, has been previously described. It was concluded that the Ru-Cl complex undergoes aquation in water and hydroxylation in basic medium, yielding the Ru-H2O aquacomplex and the Ru-OH hydroxo-complex, respectively. In addition, it has been pointed up that Ru-Cl is a bifunctional complex able to interact with DNA by external and groove binding. However, negative cyto and genotoxicity results were achieved, probably due to the formation of the hydroxo form.On the other hand, it is well known that the chloride forms in platinum and ruthenium complexes often act as prodrugs, the aqua derivatives being the most active forms. For these reasons, studying the differences related to the leaving group looks a promising challenge. The Ru-H2O compound has been isolated and purified in our laboratories. The binding mode and its properties are quite different from the chloride counterpart.The Ru-H2O interaction with CT-DNA has been studied by thermodynamic and kinetic approaches using a number of techniques: 1H NMR, 31P NMR, viscosity measurements, stopped-flow, UV-vis, fluorescence and circular dichroism spectroscopy. The sets of results gathered have shown that the Ru-H2O complex interaction mechanism is a complex process with at least three different steps: an electrostatic approximation that favours the diaminotriazine ligand intercalation into the DNA base pairs and a covalent binding, that is, a coordination of the Ru center to the phosphate group that evolves to a guanine N7 coordination. Due to these findings, it is important to explore the biological properties of this drug by means of the MTT cell proliferation assay with 96 hours exposure time in MCF-7 (human breast cancer) and A2780 (human ovarian cancer) cell lines. In both cases a dose response effect was observed. IC50 values (concentration that yields 50% inhibition of cell viability) reveal that Ru-H2O is more effective in A2780 than in MCF-7. In both cell lines, the effectiveness of the Ru complex depends on pH, being at pH 7.0 lower than at pH = 6.5 due to the amount of the hydroxo derivative formed.

The leaving group of ruthenium arene complexes plays an essential role in biological activity

BIVER, TARITA
2012

Abstract

Since the discovery of the biological activity of cisplatin, much effort has been devoted to search for other effective metallodrugs that may avoid certain problems associated to cisplatin, such as high toxicity or severe side effects. Ru (II) organometallic compounds are emerging as promising new therapeutic drugs. Cationic Ru (II) arene complexes have shown to display high antitumour activity both in vitro and in vivo. In this context, recently a new family of arene Ru (II) complexes bearing a diaminotriazine derivative have been synthesized and characterized. The DNA interaction and biological activity of one of these complexes, [RuCl(p-cymene)(қ2-N,N-2-pydaT)]BF4 denoted as Ru-Cl, has been previously described. It was concluded that the Ru-Cl complex undergoes aquation in water and hydroxylation in basic medium, yielding the Ru-H2O aquacomplex and the Ru-OH hydroxo-complex, respectively. In addition, it has been pointed up that Ru-Cl is a bifunctional complex able to interact with DNA by external and groove binding. However, negative cyto and genotoxicity results were achieved, probably due to the formation of the hydroxo form.On the other hand, it is well known that the chloride forms in platinum and ruthenium complexes often act as prodrugs, the aqua derivatives being the most active forms. For these reasons, studying the differences related to the leaving group looks a promising challenge. The Ru-H2O compound has been isolated and purified in our laboratories. The binding mode and its properties are quite different from the chloride counterpart.The Ru-H2O interaction with CT-DNA has been studied by thermodynamic and kinetic approaches using a number of techniques: 1H NMR, 31P NMR, viscosity measurements, stopped-flow, UV-vis, fluorescence and circular dichroism spectroscopy. The sets of results gathered have shown that the Ru-H2O complex interaction mechanism is a complex process with at least three different steps: an electrostatic approximation that favours the diaminotriazine ligand intercalation into the DNA base pairs and a covalent binding, that is, a coordination of the Ru center to the phosphate group that evolves to a guanine N7 coordination. Due to these findings, it is important to explore the biological properties of this drug by means of the MTT cell proliferation assay with 96 hours exposure time in MCF-7 (human breast cancer) and A2780 (human ovarian cancer) cell lines. In both cases a dose response effect was observed. IC50 values (concentration that yields 50% inhibition of cell viability) reveal that Ru-H2O is more effective in A2780 than in MCF-7. In both cell lines, the effectiveness of the Ru complex depends on pH, being at pH 7.0 lower than at pH = 6.5 due to the amount of the hydroxo derivative formed.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11568/155540
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