Antiproliferative Activities of Diimine-Based Mixed Ligand Copper(II) Complexes

A series
of Cu­(diimine)­(X-sal)­(NO3) complexes, where the diimine
is either 2,2′-bipyridine (bpy) or 1,10-phenanthroline (phen)
and X-sal is a monoanionic halogenated salicylaldehyde (X = Cl, Br,
I, or H), have been synthesized and characterized by elemental analysis
and X-ray crystallography. Penta-coordinate geometries copper­(II)
were observed for all cases. The influence of the diimine coligands
and different halogen atoms on the antiproliferative activities toward
human cancer cell lines have been investigated. All Cu­(II) complexes
were able to induce a loss of A2780 ovarian carcinoma cell viability,
with phen derivatives more active than bpy derivatives. In contrast,
no in vitro antiproliferative effects were observed against the HCT116
colorectal cancer cell line. These cytotoxicity differences were not
due to a different intracellular concentration of the complexes determined
by inductively coupled plasma atomic emission spectroscopy. A small
effect of different halogen substituents on the phenolic ring was
observed, with X = Cl being the most highly active toward A2780 cells
among the phen derivatives, while X = Br presented the lowest IC50 in A2780 cells for bpy analogs. Importantly, no reduction
in normal primary fibroblasts cell viability was observed in the presence
of bpy derivatives (IC50 > 40 μM). Mechanistically,
complex 1 seems to induce a stronger apoptotic response
with a higher increase in mitochondrial membrane depolarization and
an increased level of intracellular reactive oxygen species (ROS)
compared to complex 3. Together, these data and the low
IC50 compared to cisplatin in A2780 ovarian carcinoma cell
line demonstrate the potential of these bpy derivatives for further
in vivo studies.