Relationship between the antiproliferative properties of Cu(II) complexes with the Schiff base derived from pyridine-2-carboxaldehyde and 5,6-diamino-1,3-dimethyluracil and the redox status mediated by antioxidant defense systems on glioma tumoral cells

A set of new copper(II) complexes containing the Schiff base ligand derived from pyridine-2-carboxaldehyde and 5,6-diamino-1,3-dimethyluracil (6-amino-1,3-dimethyl-5-[(pyridin-2-ylmethylidene)-amino]-pyrimidine-2,4(1H,3H)-dione) with several anions (Cl-, Br-, I-, ClO4-, NO3-) and, two of them with 1,10-phenanthroline, were synthesized and characterized by means of elemental analysis, FT-IR, and single-crystal X-ray diffraction methods. Their ability to act as antitumor agents against C6 glioma cells has been also explored. These complexes contain copper a redox active metal essential for the regulation of cellular pathways that are fundamental for brain function. The antiproliferative activity of the complexes and their effect on cell cycle, apoptosis profile, bioenergetic behavior, intracellular reactive oxygen species (ROS) production, autophagy and enzyme antioxidant defense systems (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities) were analyzed in C6 glioma cells. Although the compounds show limited antiproliferative activity, they are able to modify S-phase of cell cycle and induce G(2)/M phase arrest. Also, copper(II) complexes promote apoptosis and, in a lesser extent, autophagy, being both processes modulated by ROS generation, due to their property to affect the enzyme antioxidant defense systems, mainly SOD and CAT but not GPx.