Chemistry and reactivity of ruthenium(II) complexes: DNA/protein binding mode and anticancer activity are related to the complex structure

In this review we summarize our work on development of Ru complexes with potential antitumor activity, which was performed over the last few years. In order to establish the structure-activity relationship for Ru(II) compounds, we have designed, synthesized and thoroughly studied several Ru(II) complexes, which were divided in three main groups: i) organometallic Ru(II)-arene complexes, ii) Ru(II) halfsandwich coordination complexes bearing neutral face-capping macrocyclic ligands, such as 1,4,7- trithiacyclononane ([9]aneS3) and 1,4,7-triazacyclononane ([9]aneN3), and iii) Ru(II)-polypyridyl complexes. Our most recent experiments moved toward synthesis, chemistry and reactivity of the heteronuclear ruthenium(II)/ferrocene complexes. The first part of the present review gives a brief overview of the structural features and anticancer activity of ruthenium complexes. The second part is focused mainly on the results obtained from the kinetic and mechanistic studies of the reactions between Ru(II) complexes and guanine derivatives, such as 9-methylguanine (9MeG), guanosine (Guo) and guanosine-50-monopho sphate (50-GMP), as well as on structural characterization of the final products of these reactions. In the final part we deal with the reactions of Ru(II) complexes with DNA, which is widely accepted as a potential target for cytotoxic ruthenium compounds. We have also described the interactions of Ru(II) compounds with the most abundant transport proteins from human serum: human serum albumin (HSA) and transferrin (Tf). We believe that a systematic review of the aforementioned studies will not only contribute to the future development of ruthenium complexes as potential antitumor agents, but will also help to understand the potential toxicity of ruthenium-based drugs.