The formation of Ni(II) complexes of GSH in conditions of 4-fold GSH excess over Ni(II) was studied by potentiometric titrations, UV-vis and CD spectroscopies, and magnetic susceptibility measurements. The following set of complexes was obtained in the pH range of 6-12: NiHL, Ni(2)L(2)(2)(-), NiHL(2)(3)(-), NiL(2)(4)(-), and NiH(-)(1)L(2)(5)(-). The first of these is an octahedral species, coordinated through the donors of the Glu moiety of GSH, while the remaining ones are largely square-planar, with participation of the thiol in Ni(II) coordination. Magnetic moments indicate the presence of a spin equilibrium for Ni(2)L(2)(2)(-), NiHL(2)(3)(-), and NiL(2)(4)(-) complexes. Phosphate ions apparently decompose the Ni(2)L(2)(2)(-) complex, converting it into a monomeric, high spin, ternary species. Among the molecular forms of GSH, HL(2)(-) is the one most susceptible to air oxidation, due to a presence of ionic interactions between its protonated amine and deprotonated thiol moieties. The complexation of Ni(II) accelerates air oxidation of GSH in alkaline solutions by a factor of 4, but this effect is absent at neutral pH. The damage to plasmid DNA by H(2)O(2) is facilitated by Ni(II) ions and inhibited by excess of GSH. However, the analysis of the concentration profile of this process indicates that octahedral Ni(II) complexes with GSH are involved in the formation of double strand breaks. Finally, numerical simulations of intracellular Ni(II) distribution, made possible by the determination of stability constants of Ni(II) complexes of GSH, indicate that histidine and ATP, rather than GSH, may act as ligands for Ni(II) in vivo. Altogether, our results suggest that the direct impact of GSH on Ni(II) toxicity may be of a limited character.

The oxidation-promoting reactivity of copper(II) complex of aminoglycosidic antibiotic amikacin [Cu(II)-Ami] in the presence of hydrogen peroxide, was studied at pH 7.4, using 2¢-deoxyguanosine (dG), pBR322 plasmid DNA and yeast tRNA Phe as target molecules. The mixtures of complex with H 2 O 2 were found to be efficient oxidants, converting dG to its 8-oxo derivative, generating strand breaks in plasmid DNA and multiple cleavages in tRNA Phe . The complex underwent autooxidation as well, with amikacin hydroperoxides as likely major products. This reactivity pattern was found to be due to a combination of metal-bound and free hydroxyl radicals.

Protonation and copper(II) coordination properties of kanamycin A were studied in solution by potentiometry, UV-Vis, circular dichroism (CD), EPR and cyclic voltammetry (CV). Only mononuclear complexes of stoichiometries ranging from CuH 2 L to CuH À2 L were found. Kanamycin A anchors Cu(II) ions with an {NH 2 , O À } chelate of the C-ring of its molecule. At pH higher than 6 the amino and hydroxyl groups of the A-ring of kanamycin A also participate in binding. The resulting structure, similar to that of complexes of other unsubstituted aminoglycosides studied previously, involves Cu(II) coordination by donors of terminal aminosugar rings, rather than those of the central unit. The results of cyclic voltammetry investigations, kinetic studies of H 2 O 2 disproportionation and ROS detection experiments, further supported the mechanism of oxidative reactivity of cupric complexes of aminoglycosides, proposed by us recently [M. Jez ˙owska-Bojczuk, W.

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