Double-strand DNA cleavage induced by oxindole-Schiff base copper(II) complexes with potential antitumor activity.
Some oxindole-Schiff base copper(II) complexes have already shown potential antitumor activity towards different cells, inducing apoptosis in a process modulated by the ligand, and having nuclei and mitochondria as main targets. Here, three novel copper(II) complexes with analogous ligands were isolated and characterized by spectroscopic techniques, having their reactivity compared to the so far most active complex in this class. Cytotoxicity experiments carried out toward human neuroblastoma SH-SY5Y cells confirmed its pro-apoptosis property. DNA cleavage studies were then performed in the presence of these complexes, in order to verify the influence of ligand structural features in its nuclease activity. All of them were able to cause double-strand DNA scissions, giving rise to nicked circular Form II and linear Form III species, in the presence of hydrogen peroxide. Additionally, DNA Form II was also detected in the absence of peroxide when the most active complex, [Cu(isaepy)2]2+ 1, was used. In an effort to better elucidate their interactions with DNA, solutions of the different complexes titrated with DNA had their absorption spectra monitored. An absorbance hyperchromism observed at 260 nm pointed to the intercalation of these complexes into the DNA structure. Further, investigations of 2-deoxy-d-ribose (DR) oxidation catalyzed by each of those complexes, using 2-thiobarbituric acid reactive species (TBARS) method, and detection of reactive oxygen species (ROS) formation by spin-trapping EPR, suggested that their mechanism of action in performing efficiently DNA cleavage occurs preferentially, but not only by oxidative pathways.
da Silveira
Vivian Chagas
VC
Departamento de Química Fundamental, Instituto de Química, Universidade de São Paulo, PO Box 26077, São Paulo, 05513-970 SP, Brazil.
Luz
Juliana Silva
JS
Oliveira
Carla Columbano
CC
Graziani
Ilaria
I
Ciriolo
Maria Rosa
MR
da Costa Ferreira
Ana Maria
AM
D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000737:chemistry*; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D003851:Deoxyribonucleases / Q000378:metabolism; D003855:Deoxyribose / Q000737:chemistry; D006801:Humans; D007211:Indoles / Q000737:chemistry; D009942:Organometallic Compounds / Q000737:chemistry*; D000078183:Oxindoles; D012545:Schiff Bases / Q000737:chemistry*; D013055:Spectrophotometry, Infrared; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D007211:Indoles; D009942:Organometallic Compounds; D000078183:Oxindoles; D012545:Schiff Bases; C022960:2-oxindole; D003855:Deoxyribose; D003300:Copper; D004247:DNA; D003851:Deoxyribonucleases