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

泰勒制造的双核配合物用于结合 DNA 主链的两个相邻磷酸盐

• 批准号: 319235505
• 负责人: Professor Dr. Dario Anselmetti
• 金额: --
• 依托单位: Arbeitsgruppe Anorganische Chemie I
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/319235505?language=en
• 关键词: Taylor; Made; Dinuclear; Complexes; Binding

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.

DNA是许多细胞毒性抗癌药物和DNA切割金属酶的靶标。通过合理的设计，合成了一类双核金属配合物，并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骨架的两个相邻磷酸酯的要求。这导致了基于2，7-二取代的1，8-萘二醇配体的前所未有的配体体系。在我们的初步工作中，可以建立合成路线，第一个配合物，双核铜（II）配合物，已经可以合成。生物化学系综方法和生物物理单分子方法的组合允许建立一个强结合的DNA伴随着低水解裂解反应性，这是出乎意料的铜（II）。此外，研究表明，与DNA的结合抑制DNA合成并导致人类癌细胞的细胞死亡-两者都比已知的抗癌药物顺铂更强。为了进一步合理的改进，我们希望建立一个结构-功能-相关性依赖于金属离子和末端配体的选择。基于金属离子和配体组，靶向两种不同的功能：1）磷酸酯键的催化裂解和2）与DNA骨架的化学稳定结合，导致细胞毒性性质。为了更深入地了解双核配合物与DNA结合的强度和效果，将应用生物化学系综方法和详细的生物物理单分子方法。在这方面，详细的和纳米力学调查的配合物的结合，DNA的AFM/STM和光/磁镊子系统计划。此外，应证明与DNA的两个相邻磷酸盐的结合。因此，将研究复合物与DNA模型系统的加合物的结晶。UHV-STM/AFM作为一种直接观察复合物与DNA磷酸盐结合的方法，将对复合物的结构进行分子解析。这些研究的最终目标是开发有效的细胞毒性药物，并确定潜在的抗癌药物进行进一步研究。