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

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)2¬Ru2Cl2(µ-Cl)¬(µ-S¬CH2-p-C6H4-NO2)] (2), and of two dinuclear p-cymene ruthenium dithiolato complexes, [(η6-p-MeC6H4Pri)2Ru2(µ-SCH2CH2Ph)2Cl2] (3) and [(η6-p-Me¬C6H4¬Pri)2¬Ru2(S¬CH2¬C6H4-p-O¬Me)2¬Cl2] (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 com¬plexes 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-Me¬C6H4¬Pri)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(µ-SR)2¬(OD)¬(CD3CN)]+ are the only spe¬cies 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)2¬Ru2{µ-SCH2CH(NH2)COOH}2(µ-SR)]+ containing two bridging cysteinato li¬gands, 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 catio¬nic trithiolato complexes containing a cysteinato bridge of this type, [(η6-p-MeC6H4Pri)2¬Ru2[µ-S¬CH2CH(NH2)COOH](µ-SCH2-p-C6H4-But)2]+ (6) could be synthesised from the di¬thiolato complex [(η6-p-Me¬C6H4¬Pri)2-Ru2(S¬CH2¬C6H4-p-But)2Cl2] (5), isolated as the tetra¬fluo¬ro¬borate 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 dithio¬lato complexes hydrolyse and react with L-cysteine. These results may have im¬portant 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.