MOE Key Laboratory of Bioinorganic and Synthetic Chemistry, State Key Laboratory of Optoelectronic Materials and Technologies, School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou, P R China.
Dalton Trans. 2013 Aug 28;42(32):11576-88. doi: 10.1039/c3dt50395j. Epub 2013 Jul 10.
Three mononuclear copper complexes [Cu(PDTP)Cl2] (PDTP = 4-phenyl-2,6-di(thiazole-2-yl)pyridine, CuPDTP), [Cu(ADTP)Cl2] (ADTP = 4-(anthracen-9-yl)-2,6-di(thiazole-2-yl)pyridine, CuADTP) and [Cu(BFDTP)Cl2] (BFDTP = 4-(benzofuran-2-yl)-2,6-di(thiazole-2-yl)pyridine, CuBFDTP) were synthesized and characterized. The X-ray single crystallography results indicated that the Cu(II) ions showed slightly distorted square pyramid coordination environments, and the ligands deviated from ideal planarity in all three compounds. Based on the DNA binding studies, it was demonstrated that these three complexes exhibited weak DNA binding strengths, which were most likely groove binding modes. CuPDTP, CuADTP and CuBFDTP induced efficient DNA cleavage in the dark without the addition of external catalysts (oxidant or reductant). In contrast, in the presence of reducing or oxidizing agents, the nuclease activities increased more than 10-fold. Mechanistic investigations revealed the participation of reactive oxygen species, which can be trapped by ROS radical scavengers and ROS sensors. In the same experimental conditions, the free ligands and CuCl2 did not display any DNA cleaving activity. This result indicates that the complexes, rather than their components, play a significant role in the nuclease reaction process and that DNA cleavage may be initiated in an oxidative pattern. The proposed mechanism was attributed to the in situ activation of molecular oxygen by the oxidation of the copper complexes. In the MTT cytotoxicity studies, the three Cu(II) complexes exhibited an antitumor activity against the HeLa, BEL-7402 and HepG2 tumor cell lines. The HeLa cells treated with Cu(II) complexes demonstrated marked changes in their nuclear morphology, which were detected by Hoechst 33258 nuclear staining and acridine orange/ethidium bromide (AO/EB) staining assays. Nuclear chromatin cleavage also was observed from alkaline single-cell gel electrophoresis (comet assay).
三种单核铜配合物[Cu(PDTP)Cl2]（PDTP=4-苯基-2,6-二（噻唑-2-基）吡啶，CuPDTP），[Cu(ADTP)Cl2]（ADTP=4-（蒽-9-基）-2,6-二（噻唑-2-基）吡啶，CuADTP）和[Cu(BFDTP)Cl2]（BFDTP=4-（苯并呋喃-2-基）-2,6-二（噻唑-2-基）吡啶，CuBFDTP）被合成并进行了表征。X 射线单晶结构结果表明，Cu(II)离子呈现出轻微扭曲的四方锥配位环境，而在所有三种化合物中，配体偏离了理想的平面性。基于 DNA 结合研究，证明这些三种配合物具有较弱的 DNA 结合强度，很可能是沟结合模式。CuPDTP、CuADTP 和 CuBFDTP 在黑暗中无需添加外部催化剂（氧化剂或还原剂）即可有效诱导 DNA 断裂。相比之下，在存在还原或氧化试剂的情况下，核酸酶活性增加了 10 多倍。机理研究表明，活性氧物种的参与可以被 ROS 自由基清除剂和 ROS 传感器捕获。在相同的实验条件下，游离配体和 CuCl2 没有显示任何 DNA 切割活性。这一结果表明，配合物而不是其成分在核酸酶反应过程中起重要作用，并且 DNA 断裂可能以氧化模式起始。提出的机制归因于铜配合物的氧化原位激活分子氧。在 MTT 细胞毒性研究中，三种 Cu(II)配合物对 HeLa、BEL-7402 和 HepG2 肿瘤细胞系表现出抗肿瘤活性。用 Cu(II)配合物处理的 HeLa 细胞显示出其核形态的明显变化，这可以通过 Hoechst 33258 核染色和吖啶橙/溴化乙锭（AO/EB）染色实验来检测。碱性单细胞凝胶电泳（彗星实验）也观察到核染色质裂解。
