Cu(II) and Zn(II) Complexes of New 8-Hydroxyquinoline Schiff Bases: Investigating Their Structure, Solution Speciation, and Anticancer Potential

We report the synthesis and characterization of threenovel Schiffbases (L1-L3) derived from the condensationof 2-carbaldehyde-8-hydroxyquinoline with amines containing morpholineor piperidine moieties. These were reacted with CuCl2 andZnCl(2) yielding six new coordination compounds, with thegeneral formula ML2, where M = Cu(II) or Zn(II) and L = L1-L3, which were all characterized byanalytical, spectroscopic (Fourier transform infrared (FTIR), UV-visibleabsorption, nuclear magnetic resonance (NMR), or electron paramagneticresonance (EPR)), and mass spectrometric techniques, as well as bysingle-crystal X-ray diffraction. In the solid state, two Cu(II) complexes,with L1 and L2, are obtained as dinuclearcompounds, with relatively short Cu-Cu distances (3.146 and3.171 & ANGS; for Cu ( 2 ) (L1) ( 4 ) and Cu ( 2 ) (L2) ( 4 ), respectively). The freeligands show moderate lipophilicity, while their complexes are morelipophilic. The pK (a) values of L1-L3 and formation constants of the complex (forML and ML2) species were determined by spectrophotometrictitrations, with the Cu(II) complexes showing higher stability thanthe Zn(II) complexes. EPR indicated the presence of several speciesin solution as pH varied and binding modes were proposed. The bindingof the complexes to bovine serum albumin (BSA) was evaluated by fluorescenceand circular dichroism (CD) spectroscopies. All complexes bind BSA,and as demonstrated by CD, the process takes several hours to reachequilibrium. The antiproliferative activity was evaluated in malignantmelanoma cells (A375) and in noncancerous keratinocytes (HaCaT). Allcomplexes display significant cytotoxicity (IC50 < 10 & mu;M) but modest selectivity. The complexes show higher activitythan the free ligands, the Cu(II) complexes being more active thanthe Zn(II) complexes, and approximately twice more cytotoxic thancisplatin. A Guava ViaCount assay corroborated the antiproliferativeactivity. Six new Cu(II) and Zn(II) 8-hydroxyquinolineSchiff basescontaining piperidine or morpholine moieties are synthesized and structurallycharacterized in the solid state and solution. The Cu(II) complexesshow higher stability than the Zn(II) complexes, as well as highercytotoxic activity against malignant melanoma.