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首页> 外文期刊>Chemistry: A European journal >A tri-copper(II) complex displaying DNA-cleaving properties and antiproliferative activity against cancer cells
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A tri-copper(II) complex displaying DNA-cleaving properties and antiproliferative activity against cancer cells

机译：三铜（II）配合物，显示出对癌细胞的切割特性和抗增殖活性

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A new disubstituted terpyridine ligand and the corresponding tri-copper(II) complex have been prepared and characterised. The binding affinity and binding mode of this tri-copper complex (as well as the previously reported mono-and di-copper analogues) towards duplex DNA were determined by using UV/Vis spectroscopic titrations and fluorescent indicator displacement (FID) assays. These studies showed the three complexes to bind moderately (in the order of 10~4 M~(-1)) to duplex DNA (ct-DNA and a 26-mer sequence). Furthermore, the number of copper centres and the nature of the substituents were found to play a significant role in defining the binding mode (intercalative or groove binding). The nuclease potential of the three complexes was investigated by using circular plasmid DNA as a substrate and analysing the products by agarose-gel electrophoresis. The cleaving activity was found to be dependent on the number of copper centres present (cleaving potency was in the order: tri-copper>di-copper>mono-copper). Interestingly, the tri-copper complex was able to cleave DNA without the need of external co-reductants. As this complex displayed the most promising nuclease properties, cell-based studies were carried out to establish if there was a direct link between DNA cleavage and cellular toxicity. The tri-copper complex displayed high cytotoxicity against four cancer cell lines. Of particular interest was that it displayed high cytotoxicity against the cisplatin-resistant MOLT-4 leukaemia cell line. Cellular uptake studies showed that the tri-copper complex was able to enter the cell and more importantly localise in the nucleus. Immunoblotting analysis (used to monitor changes in protein levels related to the DNA damage response pathway) and DNA-flow cytometric studies suggested that this tri-copper(II) complex is able to induce cellular DNA damage.
机译：已经制备并表征了新的二取代的三联吡啶配体和相应的三铜（II）配合物。通过使用UV / Vis光谱滴定和荧光指示剂置换（FID）分析，确定了这种三铜复合物（以及先前报道的单铜和双铜类似物）对双链体DNA的结合亲和力和结合方式。这些研究表明这三种复合物与双链DNA（ct-DNA和26-mer序列）适度结合（以10〜4 M〜（-1）的顺序）。此外，发现铜中心的数目和取代基的性质在限定结合模式（插入或凹槽结合）中起着重要作用。以环状质粒DNA为底物，通过琼脂糖凝胶电泳分析产物，研究了三种复合物的核酸酶潜力。发现裂解活性取决于存在的铜中心的数量（裂解能力的顺序为：三铜>二铜>单铜）。有趣的是，三铜复合物能够切割DNA，而无需外部共还原剂。由于这种复合物显示出最有希望的核酸酶特性，因此进行了基于细胞的研究，以确定DNA裂解与细胞毒性之间是否存在直接联系。三铜复合物对四种癌细胞系显示出高细胞毒性。特别令人感兴趣的是，它对顺铂耐药的MOLT-4白血病细胞系表现出高细胞毒性。细胞吸收研究表明，三铜复合物能够进入细胞，更重要的是位于细胞核中。免疫印迹分析（用于监测与DNA损伤反应途径相关的蛋白质水平的变化）和DNA流式细胞术研究表明，这种三铜（II）复合物能够诱导细胞DNA损伤。

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