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1.  DNA Oxidative Cleavage Induced by the Novel Peptide Derivatives of 3-(quinoxalin-6-yl)alanine in Combination with Cu(II) or Fe(II) Ions 
Three model dipeptides containing 3-(2,3-di(pyridin-2-yl)quinoxalin-6-yl)alanine, 3-(dipyrido[3,2-a:2,3-c]phenazin-11-yl)alanine, and 3-(2,3-diphenylquinoxalin-6-yl)alanine were studied with respect to their ability to bind selected transition metal ions, such as Cu(II), Fe(II), Ni(II), Co(II), Mn(II), and Cr(III). It was found that only Cu(II) and Fe(II) ions could form stable complex species with the studied compounds. The ability to form the complexes correlated well with DNA damage experiments. Only the ferrous and cupric complexes are capable of generating both single- and double-strand scissions. However, double-strand breakages appear to be dominating lesions in the presence of hydrogen peroxide, especially for copper(II) containing systems. The quantity of breakage products in the presence of N-(3-(dipyrido[3,2-a:2,3-c]phenazine-11-yl)alanyl)glycine complexes was the highest as compared to the complexes of the remaining compounds. Moreover, this ligand was the only one that cleaved DNA in the absence of either Cu(II) or Fe(II) ions.
PMCID: PMC2834960  PMID: 20224817
2.  Characterization of Copper(II) Interactions with Sinefungin, a Nucleoside Antibiotic: Combined Potentiometric, Spectroscopic and DFT Studies 
Interactions between sinefungin and copper(II) ions were investigated. Stoichiometry and stability constants of the metal-free system and two mononuclear complexes present in solution were determined on the basis of potentiometric data analysis. The results were compared to the Cu(II)-ornithine system due to structural similarities between both molecules. Combined spectroscopic and theoretical studies allowed for determination of coordination pattern for the Cu(II)-sinefungin complexes. At acidic pH, copper is bound in “glycine-like” coordination mode, identical with that of ornithine. This involves α-amino group and the carboxyl oxygen. At higher pH, a “bis-complex” is formed by two sinefungin molecules. The second ligand binds in equatorial position displacing two water molecules, what results in the stable {2N,2O} coordination. Both axial positions are supposed to be occupied by N1 nitrogen donors of adenine moiety, what is confirmed by DFT calculations. They interact indirectly with copper(II) through water molecules as the result of dominant syn conformation of purine.
PMCID: PMC2216065  PMID: 18273386
3.  Oxidative Activity of Copper(II) Complexes with Aminoglycoside Antibiotics as Implication to the Toxicity of These Drugs 
The majority of aminoglycosidic antibiotics anchor Cu(ll) ions by {NH2, O} chelates of the A and C rings of its molecule as distinct from amikacin, which belongs to the class of substituted ones. The results indicate that all these antibiotics effectively bind copper(ll) at physiological pH. Cyclic voltammetry investigations and kinetic studies of H2o2 disproportionation and hydroxyl radicals detection made it possible to support the mechanism of oxidative reactivity of cupric complexes of aminoglycosides, which involves Cu(1) and Cu(lll) redox states and metal-bound, rather than free radical species. The mechanism of this process appears to be complicated, and may have deleterious side-effects by leaking radical intermediates. The presence of these reactive oxygen species may be responsible for modulating the biological activity of these drugs.
The interactions of copper(ll) complexes of aminoglycosides with oxidation-susceptible biomolecules: 2’-deoxyguanosine, plasmid DNA and yeast tRNAphe in both the presence and absence of hydrogen peroxide showed that the complexes with H2o2 are the most efficient oxidants, converting dG to its 8-oxo derivative, generating strand breaks in plasmid DNA and multiple cleavages in tRNAphe. Some of these reactions may play a role in aminoglycoside-induced ototoxicity and nephrotoxicity; moreover, they may suggest that Cu(ll)-aminoglycosides are potentially dangerous genotoxic agents. These complexes were also screened for their antibacterial activity and bioassays were engaged to find out the possibility of Cu(ll)-kanamycin A complexes to induce tumor necrosis factor (TNF), interferon (IFN) and interleukin-10 (IL-10) in human peripheral blood leukocytes. The aim of these studies was to compare the biological action of antibiotic alone and complexed with copper(ll) ions in both neutral and oxidative environment.
PMCID: PMC2267070  PMID: 18365069

Results 1-3 (3)