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, [(eta(6)-p-MeC6H4Pri)(2)Ru2Cl2(mu-Cl)(mu-S-m-9-B10C2H11)] (1) and [(eta(6)-p-MeC6H4Pri)(2)Ru2Cl2(mu-Cl)(mu-SCH2-p-C6H4-NO2)] (2), and of two dinuclear p-cymene ruthenium dithiolato complexes, [(eta(6)-p-MeC(6)H(4)Pri)(2)Ru-2(mSCH(2)CH(2)Ph)(2)Cl-2] (3) and [(eta(6)-p-MeC(6)H(4)Pri)(2)Ru-2(SCH2C6H4-p-OMe)(2)Cl-2] (4) towards amino acids, nucleotides, and a single-stranded DNA dodecamer were studied using NMR and mass spectrometry. In aqueous solutions at 37 degrees 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 [(eta(6)-p-MeC(6)H(4)Pri)(2)Ru-2(OD) 2(mu-OD)(mu-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 [(eta(6)-p-MeC(6)H(4)Pri)(2)Ru-2(OD)(CD3CN)(mu-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 [(eta(6)-pMeC(6)H(4)Pr(i)) Ru-2(2){mu-SCH2CH(NH2)COOH}(2)(mu-SR)](+) containing two bridging cysteinato ligands, while 3 and 4 yield cationic trithiolato complexes [(eta(6)-p-MeC(6)H(4)Pri)(2)Ru-2[mu-SCH2CH(NH2) COOH](mu-SR)(2)](+) containing one bridging cysteinato ligand. A representative of cationic trithiolato complexes containing a cysteinato bridge of this type, [(eta(6)-p-MeC(6)H(4)Pri)(2)Ru-2[mu-SCH2CH(NH2) COOH](mu-SCH2-p-C6H4-But) 2]+ (6) could be synthesised from the dithiolato complex [(eta(6)-p-MeC(6)H(4)Pri)(2)Ru-2(SCH2C6H4-p-But)(2)Cl-2] (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.