Toward the development of metal-based synthetic nucleases: DNA binding and oxidative DNA cleavage of a mixed copper(II) complex with N-(9H-purin-6-yl)benzenesulfonamide and 1,10-phenantroline. Antitumor activity in human Caco-2 cells and Jurkat T lymphocytes. Evaluation of p53 and Bcl-2 proteins in the apoptotic mechanism.
The complex [Cu(N9-ABS)(phen)2].3.6H2O, H2N9-ABS = N-(9H-purin-6-yl)benzenesulfonamide and phen = 1,10-phenanthroline, has been synthesized and then characterized with the aid of X-ray diffraction, analytical, and spectroscopic techniques. The geometry of Cu(II) is distorted square pyramidal with the equatorial positions occupied by three N atoms from two phenantroline molecules and one N atom from the adenine ring of the sulfonamide ligand. The interaction of the complex with DNA was studied by means of viscosity measurements and fluorescence spectroscopy. The results pointed to a classic intercalation of the complex between the DNA base pairs. The complex was found to be a very efficient agent of plasmid DNA cleavage in the presence of ascorbate. Both the kinetics and the mechanism of the cleavage reaction were studied. In addition, the cytotoxic properties of the complex were evaluated in human Jurkat T and Caco-2 cell lines. The cytotoxicity of the compound was higher than that of the reference ([Cu(phen)2]2+). The mechanism and type of cell death induced by the compound was determined by flow cytometry and Hoechst dye staining. The compound demonstrated a significant ability to induce cell death by apoptosis. The apoptosis induced by [Cu(N9-ABS)(phen)2].3.6H2O was associated with an increase in p53 protein levels while those of Bcl-2 were reduced.
Departament de Química Inorgànica, Facultat de Farmàcia, Universitat de València, 46100 Burjassot, Spain.
José Luis
JL
García-Giménez
Marta
M
González-Alvarez
Malva
M
Liu-González
Benigno
B
Macías
Joaquín
J
Borrás
Gloria
G
Alzuet
D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D018938:Caco-2 Cells; D003300:Copper / Q000737:chemistry*; D004247:DNA / Q000378:metabolism*; D053837:DNA Cleavage / Q000187:drug effects*; D006801:Humans; D019169:Jurkat Cells; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D010618:Phenanthrolines / Q000737:chemistry; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D013449:Sulfonamides / Q000737:chemistry; D016159:Tumor Suppressor Protein p53 / Q000032:analysis; D000096926:Benzenesulfonamides
D000970:Antineoplastic Agents; D003300:Copper; D004247:DNA; D009942:Organometallic Compounds; D010618:Phenanthrolines; D019253:Proto-Oncogene Proteins c-bcl-2; D013449:Sulfonamides; D016159:Tumor Suppressor Protein p53; D000096926:Benzenesulfonamides; C025205:1,10-phenanthroline