Dinuclear copper(II) complexes with a bridging bis(chalcone) ligand reveal considerable in vitro cytotoxicity on human cancer cells and enhanced selectivity

A bis(chalcone) molecule (H2L) was synthesized via Aldol's condensation from terephthalaldehyde and 2 ' hydroxyacetophenone and it was used as bridging ligand for the preparation of five dinuclear copper(II) complexes of the composition [Cu(N-N)(mu-L)Cu(N-N)](NO3)2 & sdot;nH2O (n = 0-2) (1-5), where N-N stands for a bidentate N-donor ligand such as phen (1,10-phenanthroline, 1), bpy (2,2 '-bipyridine, 2), mebpy (5,5 '-dimethyl2,2 '-dipyridine, 3), bphen (bathophenanthroline, 4) and nphen (5-nitro-1,10-phenanthroline, 5). The compounds were characterized by different suitable techniques to confirm their purity, composition, and structure. Moreover, the products were evaluated for their in vitro cytotoxicity on a panel of human cancer cell lines: ovarian (A2780), ovarian resistant to cisplatin (A2780R), prostate (PC3), osteosarcoma (HOS), breast (MCF7) and lung (A549), and normal fibroblasts (MRC-5), showing significant cytotoxicity in most cases, with IC50 approximate to 0.35-7.8 mu M. Additionally, the time-dependent cytotoxicity and cellular uptake of copper, together with flow cytometric studies concerning cell-cycle arrest, induction of cell death and autophagy and induction of intracellular ROS/ superoxide production in A2780 cells, were also performed. The results of biological testing on A2780 cells pointed out a possible mechanism of action characterized by the G2/M cell cycle arrest and induction of apoptosis by triggering the intrinsic signalling pathway associated with the damage of mitochondrial structure and depletion of mitochondrial membrane potential.
Synopsis: Dinuclear Cu(II) complexes bearing a bridging bis(chalcone) ligand revealed high in vitro cytotoxicity, initiated A2780 cell arrest at G2/M phase and efficiently triggered intrinsic pathway of apoptosis.