Ruthenium compounds have become promising alternatives to platinum drugs by displaying specific activities against different cancers and favourable toxicity and clearance properties. Nonetheless, their molecular targeting and mechanism of action are poorly understood. Here we study two prototypical ruthenium-arene agents-the cytotoxic antiprimary tumour compound [(η(6)-p-cymene)Ru(ethylene-diamine)Cl]PF6 and the relatively non-cytotoxic antimetastasis compound [(η(6)-p-cymene)Ru(1,3,5-triaza-7-phosphaadamantane)Cl2]-and discover that the former targets the DNA of chromatin, while the latter preferentially forms adducts on the histone proteins. Using a novel 'atom-to-cell' approach, we establish the basis for the surprisingly site-selective adduct formation behaviour and distinct cellular impact of these two chemically similar anticancer agents, which suggests that the cytotoxic effects arise largely from DNA lesions, whereas the protein adducts may be linked to the other therapeutic activities. Our study shows promise for developing new ruthenium drugs, via ligand-based modulation of DNA versus protein binding and thus cytotoxic potential, to target distinguishing epigenetic features of cancer cells.

Platinum complex-based chemotherapy is one of the major treatment options of many malignancies. Although severe side effects occur, and only a limited spectrum of tumors can be cured, Pt compounds are used in every second therapy scheme. Thus, many different drug design strategies have been employed for improving the properties of anticancer drugs including pH or redox activation in the tumor, variation of the metal center and therefore the redox and ligand exchange properties, the application of multinuclear metal complexes, the development of targeted approaches, etc. Application of carbohydrate – metal complexes is an example of a targeted approach exploiting the biochemical and metabolic functions of diverse sugars in living organisms for transport and accumulation. Natural carbohydrates and synthetic derivatives possess a manifold of donors endowing them with the ability to coordinate metal centers and providing some additional advantages over other ligands, e.g., biocompatibility, non-toxicity, enantiomeric purity, water solubility, and wellexplored chemistry. In recent years, several examples of carbohydrate compounds have been developed for diverse medicinal applications ranging from compounds with antibiotic, antiviral, or fungicidal activity and anticancer compounds. Herein, metal complexes with carbohydrate ligands are reviewed and the role of the carbohydrate carriers on the antineoplastic activity of these compounds, both in vitro and in vivo, is described.