Taylor-Made Dinuclear Complexes for Binding at two Neighboring Phosphates of the DNA Backbone

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DNA is the target of many cytotoxic anticancer-drugs and DNA-cleaving metalloenzymes. Based on a rational design, a family of dinuclear metal complexes has been developed for the binding to DNA by a novel binding mode. As most of the known cytotoxic drugs bind to the nucleobases of DNA, our rational design is based on the request to bind at two neighboring phosphate esters of the DNA backbone. This resulted in an unprecedented ligand system based on 2,7-disubstituted 1,8-naphthalindiol ligands. In our preliminary work a synthetic route could be established and the first complex, a dinuclear copper(II) complex, could already be synthesized. The combination of biochemical ensemble methods and biophysical single-molecule methods allowed to establish a strong binding to the DNA accompanied by a low hydrolytic cleavage reactivity, which was unexpected for copper(II). Furthermore it was shown, that the binding to the DNA inhibits the DNA synthesis and results in the cell death of human cancer cells - both in a stronger fashion than the known anticancer drug cisplatin. For a further rational improvement, we want to establish a structure-function-correlation in dependence on the choice of the metal ions and the terminal ligands. Based on the metal ion and the ligand set, two different functionalities are targeted: 1) catalytic cleavage of phosphorester bonds and 2) thermodynamically stable binding to the DNA backbone resulting in cytotoxic properties. In order to gain more insight into the strength and the effect of the binding of the dinuclear complexes to DNA, biochemical ensemble methods and elaborated biophysical single molecule methods will be applied. In this respect, a detailed and nanomechanical investigation of the binding of the complexes to DNA by AFM/STM and optical/magnetic tweezer systems is planned. Furthermore, the binding to two neighboring phosphates of the DNA should be proven. Therefore, the crystallization of adducts of the complexes to DNA model systems will be investigated. As a direct method to observe the binding of the complexes to the phosphates of DNA, the structure will be resolved molecularly by UHV-STM/AFM. The final goal of these studies is the development of potent cytotoxic drugs and the identification of potential anticancer drugs for further investigations.