RESUMO
Three novel copper(II) complexes CuL(1)Cl2 (1) (L(1)=4'-(3-methoxyphenyl)-2,2':6'- 2â³-terpyridine), CuL(2)Cl2 (2) (L(2)=4'-(4-methoxyphenyl)-2,2':6'-2â³-terpyridine) and CuL(3)Cl2 (3) (L(3)=4'-(3,5-dimethoxyphenyl)-2,2':6'-2â³-terpyridine) have been synthesized and characterized. Absorption spectral titration experiments, ethidium bromide displacement assays, and cyclic voltammetric experiments were carried out and the results suggested that these complexes bound to DNA through an intercalative mode. Moreover, these complexes were found to cleave pBR322 DNA efficiently in the presence of glutathione (GSH), and exhibited good anticancer activity against HeLa, Hep-G2 and BEL-7402 cell lines. Nuclear chromatin cleavage was also observed by acridine orange/ethidium bromide (AO/EB) staining assays and comet assays. These results demonstrated that these three Cu(II) complexes caused DNA damage and induced the apoptosis of HeLa cells. Mechanistic investigations revealed the participation of reactive oxygen species which can be trapped by reactive oxygen species (ROS) radical scavengers and ROS sensors.
Assuntos
Antineoplásicos/síntese química , Complexos de Coordenação/síntese química , Cobre/química , Citotoxinas/síntese química , Substâncias Intercalantes/síntese química , Piridinas/química , Animais , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Cátions Bivalentes , Bovinos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaio Cometa , Complexos de Coordenação/farmacologia , Citotoxinas/farmacologia , DNA/química , Fragmentação do DNA/efeitos dos fármacos , Glutationa/metabolismo , Humanos , Substâncias Intercalantes/farmacologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Three new tridentate copper(II) complexes [Cu(dthp)Cl(2)] (1) (dthp=2,6-di(thiazol-2-yl)pyridine), [Cu(dmtp)Cl(2)] (2) (dmtp=2,6-di(5-methyl-4H-1,2,4-triazol-3-yl)pyridine) and [Cu(dtp)Cl(2)] (3) (dtp=2,6-di(4H-1,2,4-triazol-3-yl)pyridine) have been synthesized and characterized. Crystal structure of complex 1 shows that the complex existed as distorted square pyramid with five co-ordination sites occupied by the tridentate ligand and the two chlorine anions. Ethidium bromide displacement assay, viscosity measurements, circular dichroism studies and cyclic voltammetric experiments suggested that these complexes bound to DNA via an intercalative mode. Three Cu(II) complexes were found to efficiently cleave DNA in the presence of sodium ascorbate, and singlet oxygen ((1)O(2)) and hydrogen peroxide were proved to contribute to the DNA cleavage process. They exhibited anticancer activity against HeLa, Hep-G2 and BEL-7402 cell lines. Nuclear chromatin cleavage has also been observed with AO/EB staining assay and the alkaline single-cell gel electrophoresis (comet assay). The results demonstrated that three Cu(II) complexes cause DNA damage that can induce the apoptosis of BEL-7402 cells.
