Structure, cytotoxicity, and DNA-cleavage properties of the complex [CuII(pbt)Br2]

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.