Copper(II) Complexes of Phenanthroline and Histidine Containing Ligands: Synthesis, Characterization and Evaluation of their DNA Cleavage and Cytotoxic Activity

Copper­(II) complexes have been intensely
investigated in a variety of diseases and pathological conditions
due to their therapeutic potential. The development of these complexes
requires a good knowledge of metal coordination chemistry and ligand
design to control species distribution in solution and tailor the
copper­(II) centers in the right environment for the desired biological
activity. Herein we present the synthesis and characterization of
two ligands HL1 and H2L2 containing a phenanthroline unit
(phen) attached to the amino group of histidine (His). Their copper­(II)
coordination properties were studied using potentiometry, spectroscopy
techniques (UV–vis and EPR), mass spectrometry (ESI-MS) and
DFT calculations. The data showed the formation of single copper complexes,
[CuL1]+ and [CuL2], with high stability within a large
pH range (from 3.0 to 9.0 for [CuL1]+ and from 4.5 to 10.0
for [CuL2]). In both complexes the Cu2+ ion is bound to
the phen unit, the imidazole ring and the deprotonated amide group,
and displays a distorted square pyramidal geometry as confirmed by
single crystal X-ray crystallography. Interestingly, despite having
similar structures, these copper complexes show different redox potentials,
DNA cleavage properties and cytotoxic activity against different cancer
cell lines (human ovarian (A2780), its cisplatin-resistant variant
(A2780cisR) and human breast (MCF7) cancer cell lines). The [CuL2]
complex has lower reduction potential (Epc= −0.722 V vs −0.452 V for [CuL1]+) but
higher biological activity. These results highlight the effect of
different pendant functional groups (carboxylate vs amide), placed
out of the coordination sphere, in the properties of these copper
complexes.