Artificial metallonucleases with pyrrole- and pyridine-based ligand platforms

• Applicant: Professorin Dr. Nora Kulak
• Subject Area: Biological and Biomimetic Chemistry
• Term: from 2012 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 233311964

Besides of widely used organic molecules, also some metal-based compounds are applied in chemotherapy. The most important compound among the latter ones is the metal complex cisplatin, which can cause cytotoxicity by binding to DNA in the cell nucleus. A lack of selectivity for cancer cells, however, often leads to systemic toxicity and thus severe side-effects.Cytotoxicity of metal complexes can be a consequence not only of DNA binding but also of DNA cleavage. Thus the focus of this research program lies on the design of artificial metallonucleases that act as DNA cleaving agents, similar to their natural models.The basis of the nucleases presented here are Cu(II) complexes with new ligand systems relying on pyrrole and pyridine platforms. DNA cleavage will be examined using models in cell-free systems, and subsequently the complexes will be tested in in vitro cell studies. In order to achieve selectivity for cancer cells, the ligand systems will be equipped with targeting moieties, and Cu concentration differences in diseased and healthy cells will be exploited. It will then be investigated if cytotoxicity and DNA cleavage activity of the Cu(II) compounds can be correlated.This kind of correlation of experiments on the molecular and cell biological level has not been evaluated thoroughly so far for Cu complexes. This is in contrast to the well studied Pt complexes like cisplatin, whose biological action is thus better understood. Filling this gap in the field opens up possibilities for understanding the biological activity of Cu(II)-based compounds and provides a basis for the rational design of Cu(II)-based chemotherapeutics.

• DFG Programme: Research Grants