Arene control over thiolate to sulfinate oxidation in albumin by organometallic ruthenium anticancer complexes.

Interactions of organometallic ruthenium anticancer complexes [Ru(eta6-arene)Cl(en)][PF6] (arene=p-cymene (1) or biphenyl (2), en=ethylenediamine) with human serum albumin were investigated by means of mass spectrometry combined with trypsin digestion, specific sidechain modifications and computational modelling. Both complexes were shown to bind to surface histidine (His128, His247, His510) and methionine (Met298) residues in human albumin, but only the p-cymene complex can gain entry to the crevice containing the free cysteine thiolate (Cys34) and induce oxidation to sulfinate. The two complexes exhibit a similar coordination preference for histidine and methionine residues on the protein surface. His128 binding is favoured both kinetically and thermodynamically. At 310 K, six days of incubation of recombinant human albumin (rHA) with complex 1 (rHA:Ru 50:250 microM) led to about 18 % ruthenation of His128 in the protein. However, the extent of ruthenation of albumin by complex 2 was less than that by 1, due to the steric hindrance from the biphenyl ligand. These results imply that the arene ligand in the organometallic ruthenium anticancer complexes plays a crucial role in interactions with proteins.