Hydrolytic behaviour of mono- and dithiolato-bridged dinuclear arene ruthenium complexes and their interactions with biological ligands

Abstract

The hydrolysis and the reactivity of two dinuclear p-cymene ruthenium monothiolato complexes, [(η6-p-MeC6H4Pri)2Ru2Cl2(μ-Cl)(μ-S-m-9-B10C2H11)] (1) and [(η6-p-MeC6H4Pri)2Ru2Cl2(μ-Cl)(μ-SCH2-p-C6H4-NO2)] (2), and of two dinuclear p-cymene ruthenium dithiolato complexes, [(η6-p-MeC6H4Pri)2Ru2(μ-SCH2CH2Ph)2Cl2] (3) and [(η6-p-MeC6H4Pri)2Ru2(SCH2C6H4-p-OMe)2Cl2] (4) towards amino acids, nucleotides, and a single-stranded DNA dodecamer were studied using NMR and mass spectrometry. In aqueous solutions at 37°C, the monothiolato complexes 1 and 2 undergo rapid hydrolysis, irrespective of the pH value, the predominant species in D2O/acetone-d6 solution at equilibrium being the neutral hydroxo complexes [(η6-p-MeC6H4Pri)2Ru2(OD)2(μ-OD)(μ-SR)]. The dithiolato complexes 3 and 4 are stable in water under acidic conditions, but undergo slow hydrolysis under neutral and basic conditions. In both cases, the cationic hydroxo complexes [(η6-p-MeC6H4Pri)2Ru2(OD)(CD3CN)(μ-SR)2]+ are the only species observed in D2O/CD3CN at equilibrium. Surprisingly, no adducts are observed upon addition of an excess of l-methionine or l-histidine to the aqueous solutions of the complexes. Upon addition of an excess of l-cysteine, on the other hand, 1 and 2 form the unusual cationic trithiolato complexes [(η6-p-MeC6H4Pri)2Ru2{μ-SCH2CH(NH2)COOH}2(μ-SR)]+ containing two bridging cysteinato ligands, while 3 and 4 yield cationic trithiolato complexes [(η6-p-MeC6H4Pri)2Ru2[μ-SCH2CH(NH2)COOH](μ-SR)2]+ containing one bridging cysteinato ligand. A representative of cationic trithiolato complexes containing a cysteinato bridge of this type, [(η6-p-MeC6H4Pri)2Ru2[μ-SCH2CH(NH2)COOH](μ-SCH2-p-C6H4-But)2]+ (6) could be synthesised from the dithiolato complex [(η6-p-MeC6H4Pri)2Ru2(SCH2C6H4-p-But)2Cl2] (5), isolated as the tetrafluoroborate salt and fully characterised. Moreover, the mono- and dithiolato complexes 1-4 are inert toward nucleotides and DNA, suggesting that DNA is not a target of cytotoxic thiolato-bridged arene ruthenium complexes. In contrast to the trithiolato complexes, monothiolato and dithiolato complexes hydrolyse and react with l-cysteine. These results may have important implications for the mode of action of thiolato-bridged dinuclear arene ruthenium drug candidates, and suggest that their modes of action are different to those of other arene ruthenium complexes.