Synthesis, characterization and potent superoxide dismutase-like activity of novel bis(pyrazole)-2,2'-bipyridyl mixed ligand copper(II) complexes

• Published in: Dalton transactions : an international journal of inorganic chemistry 2009-01 (23), p.4488-4498
• Main Authors: Potapov, Andrei S, Nudnova, Evgenia A, Domina, Galina A, Kirpotina, Liliya N, Quinn, Mark T, Khlebnikov, Andrei I, Schepetkin, Igor A
• Format: Article
• Language: English
• Subjects: 2,2'-Dipyridyl - chemistry; Animals; Biomimetic Materials - chemical synthesis; Biomimetic Materials - chemistry; Biomimetic Materials - metabolism; Biomimetic Materials - pharmacology; Cattle; Cell Line; Cell Proliferation - drug effects; Cell Survival - drug effects; Copper - chemistry; Crystallography, X-Ray; Electrochemistry; Electrons; Free Radical Scavengers - metabolism; Humans; Ligands; Mice; Models, Molecular; Molecular Conformation; Organometallic Compounds - chemical synthesis; Organometallic Compounds - chemistry; Organometallic Compounds - metabolism; Organometallic Compounds - pharmacology; Quantum Theory; Spectrum Analysis; Superoxide Dismutase - metabolism
• ISSN: 1477-9226; 1477-9234
• DOI: 10.1039/b900869a

Eleven new complexes of Cu(II) chloride and nitrate with bis(pyrazol-1-yl)propane and bis[2-(pyrazol-1-yl)ethyl]ether ligands were prepared and characterized by spectral and electrochemical methods. X-Ray crystal structure determination of bis[2-(3,5-dimethylpyrazol-1-yl)ethyl]etherdinitratocopper revealed a hepta-coordinated structure with the bis(pyrazole) ligand coordinated in a tridentate NNO-fashion and both of the nitrate ions in a bidentate fashion. Reaction of Cu(II) nitrate complexes with 2,2'-bipyridyl led to the displacement of one of the nitrate ions into the outer sphere and the formation of mixed-ligand complexes. Mixed-ligand bipyridyl Cu(II) complexes demonstrated the highest superoxide dismutase (SOD)-like activity in a chemical superoxide anion-generating system, with IC(50) values in the low micromolar range. Density functional theory calculations showed that introduction of a bipypidyl ligand into the complexes dramatically lowered the lowest unoccupied molecular orbital (LUMO) energy level, which explains the increased SOD-like activity of these complexes compared to non-bipy species. These bipy complexes were also effective scavengers of reactive oxygen species generated by phagocytes (human neutrophils and murine bone marrow leukocytes) ex vivo. Thus, these bipy mixed-ligand complexes represent a promising class of SOD mimetics for future development.