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-Bu^t)₂]⁺ (6) could be synthesised from the dithiolato complex [(η⁶-p-MeC₆H₄Prⁱ)₂Ru₂(SCH₂C₆H₄-p-Bu^t)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.