Nucleic acids play a crucial role in cellular processes, as they are key elements responsible for storage and replication of the genetic information and its conversion into proteins. Moreover, they perform manifold regulatory and catalytic activities. Thus, it is not surprising that nucleic acids and especially their biologically relevant higher-order structures, such as duplexes and quadruplexes have gained increased attention as targets for the treatment of gene-related diseases. Among DNA-targeting drugs, cis-dichlorodiamineplatinum(II), known as cisplatin, was the first transition metal-based compound to be introduced as anti-tumor agent and it has been administered for the successful treatment of various types of cancer to this day. Unfortunately, the therapy provokes severe side effects, which triggered the search for alternative agents. Second and third generation platinum-based chemotherapeutics aim at increased selectivity of the drugs as well as improved delivery to their targets. While compounds based on substitute transition metals, namely ruthenium, are currently evaluated for their anti-proliferative activity against tumor cells as well, platinum-based agents remain unique in that their principal target in the cell is DNA.
With this background, the proposed research aims at the investigation of the interaction of platinum- and ruthenium-based complexes with higher-order nucleic acids in order to elucidate the selectivities, affinities, and binding motifs of the metallodrugs. Such information is required to assess potential nucleic acid targets of drug candidates, to draw conclusions about their structure-activity relationships, and to assist the future development of tailored, more selective-acting anticancer drugs. Though still in its infancy, tandem mass spectrometry of nucleic acid - drug adducts harbors a great potential in the field of gene-related diseases and results will broaden our understanding of the mode of action of transition metal-based therapeutics.