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

DNA是许多细胞毒性抗癌药物和DNA切割金属酶的靶点。在合理设计的基础上，开发了一类双核金属配合物，以一种新的结合方式与DNA结合。由于大多数已知的细胞毒性药物与DNA的核碱基结合，我们的合理设计是基于结合DNA主链的两个相邻磷酸酯的要求。这导致了一个前所未有的基于2,7-二取代1,8-萘二醇配体的配体体系。在我们的初步工作中，我们可以建立一个合成路线，并已经合成了第一个配合物，一个双核铜（II）配合物。结合生物化学集成方法和生物物理单分子方法，可以建立与DNA的强结合，同时具有较低的水解裂解反应性，这是铜（II）意想不到的。此外，研究表明，与DNA的结合抑制了DNA合成，导致人类癌细胞的细胞死亡——这两种方式都比已知的抗癌药物顺铂更强烈。为了进一步合理改进，我们希望建立依赖于金属离子和末端配体选择的结构-功能相关性。基于金属离子和配体集，有两种不同的功能：1)催化磷酸酯键的裂解和2)与DNA主链的热力学稳定结合，从而产生细胞毒性。为了更深入地了解双核复合物与DNA结合的强度和效果，将应用生化集成方法和详细的生物物理单分子方法。在这方面，计划通过AFM/STM和光学/磁镊子系统对复合物与DNA的结合进行详细的纳米力学研究。此外，与DNA的两个相邻磷酸的结合应该被证明。因此，对DNA模型系统的配合物加合物的结晶将进行研究。作为一种直接观察复合物与DNA磷酸盐结合的方法，该结构将通过UHV-STM/AFM进行分子解析。这些研究的最终目标是开发有效的细胞毒性药物和鉴定潜在的抗癌药物，以供进一步研究。

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.