Structure, cytotoxicity, and DNA-cleavage properties of the complex [CuII(pbt)Br2]
Structure, cytotoxicity, and DNA-cleavage properties of the complex [CuII(pbt)Br2]
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DOI：
10.1021/ic702306f
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发表时间：
2008-05-05
影响因子：
4.6
通讯作者：
Reedijk, Jan
中科院分区：
文献类型：
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作者：
Maheswari, Palanisamy Uma;van der Ster, Martijn;Reedijk, Jan
在乙腈中，配体2-（2-吡啶基）苯并噻唑（pbt）分别与CuBr_2和ZnCl_2反应生成配合物[Cu（pbt）Br-2]（1）和[Zn（pbt）Cl-2]（3）。将配合物1溶于DMF中，得到配合物2，为浅绿色晶体。pbt与CuBr_2在DMF中反应也得到配合物[Cu（pbt）Br_2（dmf）]（2）（dmf =二甲基甲酰胺）。配合物1-3通过X射线晶体学表征。配合物1和3具有扭曲的四面体配位环境，配合物2由两个略有不同的铜中心组成，都表现出扭曲的三角双锥几何结构。复合物1和2在存在和不存在还原剂的情况下切割phi X174噬菌体DNA。游离配体pbt不显示任何DNA切割能力。络合物3的溶解性差，使其不适用于生物试验。在各种自由基清除剂存在下DNA断裂的发生表明，没有可扩散的自由基参与复合物1的DNA切割，因为没有清除剂抑制切割反应。DNA切割产物不与酶T4 DNA连接酶连接，这是切割是非水解的额外证据。最可能的裂解反应涉及活性氧，不能被捕获，导致氧化机制。在类似的电化学条件下，Cu-II（pbt）Br-2在DMF中容易氧化成Cu-III并还原成Cu-I可导致分子氧的原位活化，导致形成能够促进DNA氧化裂解的金属溶剂化的不可扩散自由基。配合物1和纯配体对癌细胞系L1210和A2780以及这些细胞系的相应顺铂抗性突变体表现出显著的细胞毒作用。
The reactions of the ligand 2-(2-pyridyl)benzthiazole (pbt) with CuBr2 and ZnCl2 in acetonitrile produce the complexes [Cu(pbt)Br-2] (1) and [Zn(pbt)Cl-2] (3), respectively. When complex 1 is dissolved in DMF, complex 2 is obtained as light-green crystals. The reaction of pbt with CuBr2 in DMF also yields the complex [Cu(pbt)Br-2(dmf)] (2) (dmf = dimethylformamide). Complexes 1-3 were characterized by X-ray crystallography. Complexes 1 and 3 have distorted tetrahedral coordination environments, and complex 2 is constituted of two slightly different copper centers, both exhibiting distorted trigonal bipyramidal geometries. Complexes 1 and 2 cleave phi X174 phage DNA, both in the presence and the absence of reductant. The free ligand pbt does not show any DNA-cleaving abilities. The poor solubility of complex 3 makes it not applicable for biological tests. The occurrence of DNA breaks in the presence of various radical scavengers suggests that no diffusible radicals are involved in the DNA cleavage by complex 1, as none of the scavengers inhibit the cleavage reaction. The DNA-cleavage products are not religated with the enzyme T4 DNA ligase, which is an additional proof that the cleavage is nonhydrolytic. Most probably the cleaving reaction involves reactive oxygen species, which could not be trapped, leading to an oxidative mechanism. An easy oxidation of Cu-II(pbt)Br-2 to Cu-III in DMF and the reduction of the same to Cu-I, under similar electrochemical conditions may lead to the in situ activation of molecular oxygen, resulting in the formation of metal solvated nondiffusible radicals able to prompt the oxidative cleavage of DNA. Complex 1 and the pure ligand exhibit remarkable cytotoxic effects against the cancer cell lines L1210 and A2780 and also against the corresponding cisplatin-resistant mutants of these cell lines.