Water-soluble copper(II) complexes with 4,5-dichloro-isothiazole-3-carboxylic acid and heterocyclic N-donor ligands: synthesis, crystal structures, cytotoxicity, and DNA binding study

Abstract Mixed-ligand copper(II) complexes based on 1,10-phenanthroline and related compounds are of interest to scientists due to their promising anticancer properties. In this study, four new water-soluble copper(II) complexes [Cu(dmbipy)L2], [Cu(phen)(H2O)L2], [Cu(dmphen)L2] and [Cu2(bipy)2L4], where HL – 4,5-dichloro-isothiazole-3-carboxylic acid, bipy –2,2’-bipyridine, dmbipy – 2,2’-bi-4-picoline, phen – 1,10-phenanthroline, dmphen – 4,7-dimethyl-1,10-phenanthroline are reported. All complexes have been characterized by elemental and powder X-ray diffraction analysis, EPR and IR-spectroscopy. Molecular structures of the reported complexes have been determined by single crystal X–ray diffraction. Copper(II) ion, HL and heterocyclic N-donor ligands have been found to form 1:2:1 complexes that possess square bipyramid or square pyramidal geometry. The UV-vis spectroscopy and mass spectrometry have been applied to show the behavior of the compounds in solution. All complexes have been screened in vitro for their cytotoxic activity against Hep-2 and MCF-7 cell lines. They exhibit significant dose-dependent cytotoxic effect and [Cu(dmphen)L2] is found to be the most cytotoxic (IC50 = 0.97 ± 0.03 µM when compared to IC50 = 9.2 ± 0.5 µM for control, cisplatin – Hep-2 cell line). The investigation of DNA binding ability by UV-vis titration technique indicates that complexes obtained exhibit moderate binding affinity toward calf Thymus DNA. Effect of [Cu(dmbipy)L2] and [Cu(dmphen)L2] on activity of drug-metabolizing enzymes cytochromes P450 has also been investigated. The addition of complexes to the hepatic microsomes of 3-MC or PB-treated rat, lead to a dose-dependent decrease of CYP’s activities. The data obtained indicate that [Cu(dmphen)L2] and [Cu(phen)(H2O)L2] can be potential anticancer agents.