Biological and cytoselective anticancer properties of copper(II)-polypyridyl complexes modulated by auxiliary methylated glycine ligand

Abstract

A series of ternary copper(II)-1,10-phenanthroline complexes with glycine and methylated glycine derivatives, [Cu(phen)(aa)(H2O)]NO3·xH2O 1–4 (amino acid (aa): glycine (gly), 1; dl-alanine (dl-ala), 2; 2,2-dimethylglycine (C-dmg), 3; sarcosine (sar), 4), were synthesized and characterized by FTIR, elemental analysis, electrospray ionization–mass spectra (ESI–MS), UV–visible spectroscopy and molar conductivity measurement. The determined X-ray crystallographic structures of 2 and 3 show each to consist of distorted square pyramidal [Cu(phen)(aa)(H2O)]+ cation, a nitrate counter anion, and with or without lattice water, similar to previously reported structure of [Cu(phen)(gly)(H2O)]NO3·1½H2O. It is found that 1–4 exist as 1:1 electrolytes in aqueous solution, and the cationic copper(II) complexes are at least stable up to 24 h. Positive-ion ESI–MS spectra show existence of only undissociated [Cu(phen)(aa)]+ species. Electron paramagnetic resonance, gel electrophoresis, fluorescence quenching, and restriction enzyme inhibition assay were used to study the binding interaction, binding affinity and selectivity of these complexes for various types of B-form DNA duplexes and G-quadruplex. All complexes can bind selectively to DNA by intercalation and electrostatic forces, and inhibit topoisomerase I. The effect of the methyl substituents of the coordinated amino acid in the above complexes on these biological properties are presented and discussed. The IC50 values (24 h) of 1–4 for nasopharyngeal cancer cell line HK1 are in the range 2.2–5.2 μM while the corresponding values for normal cell line NP69 are greater than 13.0 μM. All complexes, at 5 μM, induced 41–60 % apoptotic cell death in HK1 cells but no significant cell death in NP69 cells.