Use of chelating ligands to tune the reactive site of half-sandwich ruthenium(II)-arene anticancer complexes

We show that the chelating ligand XY in Ru-11 anticancer complexes of the type [Ru(eta(6)-arene)(XY)Cl](n+) has a major influence on the rate and extent of aquation, the pK(a), of the aqua adduct, and the rate and selectivity of binding to nucleobases. Replacement of neutral ethylenediamine (en) by anionic acetylacetonate (acac) as the chelating ligand increases the rate and extent of hydrolysis, the pK(a), of the aqua complex (from 8.25 to 9.41 for arene = p-cymene), and changes the nucleobase specificity. For the complexes containing the hydrogen-bond donor en, there is exclusive binding to N7 of guanine in competitive nucleobase reactions, and in the absence of guanine, binding to cytosine or thymine but not to adenine. In contrast, when XY is the hydrogen-bond acceptor acac, the overall affinity for adenosine (N7 and N1 binding) is comparable to that for guanosine, but there is little binding to cytidine or thymidine.