Novel Mixed-Ligand Copper(I) Complexes: Role of Diimine Ligands on Cytotoxicity and Genotoxicity

Novel
tetrahedral copper­(I) mixed-ligand complexes of the type
[Cu­(X)­(N∩N)­(PCN)], 3–10, where X = Cl or Br, N∩N = 2,2′-bipyridine
(bipy), 1,10-phenanthroline (phen), 5,6-dimethyl-1,10-phenanthroline
(dmp), and dipyrido-[3,2-d:2′,3′-f]-quinoxaline (dpq), and PCN = tris-(2-cyanoethyl)­phosphine,
have been synthetized and characterized by NMR, ESI-MS, and X-ray
diffraction on two representative examples, [CuCl­(phen)­(PCN)]·DMF
(5·DMF) and [CuBr­(dpq)­(PCN)]·2DMF (10·2DMF). Cu­(I) complexes were evaluated for their in vitro antitumor
properties against a panel of human cancer cell lines, including cisplatin-
and multidrug-resistant sublines. The most effective complex, [CuCl­(dpq)­(PCN)]
(9), exhibited nanomolar cytotoxicity toward both sensitive
and resistant cancer cells, but it significantly inhibited the growth
of cultured normal cells. In vitro DNA assays and single cell gel
electrophoresis revealed that 9 induced DNA fragmentation
resulting in cell apoptosis. In parallel, fluorescence in situ hybridization
(FISH) micronucleus assay attested high levels of genotoxicity following
treatment of peripheral blood lymphocytes with complex 9, suggesting that the potential risk posed by diimine metal complexes
should be carefully reconsidered.