Use of SDS micelles to stabilize a ternary intermediate in the reaction of ferrioxamine B and 1,10-phenanthroline.

Spectrophotometric measurements of the reaction of ferrioxamine B (FeHDFB(+)) with 1,10-phenanthroline (phen) reveal the presence of a ternary intermediate complex in both aqueous solution and an aqueous solution of 0.16 M sodium dodecyl sulfate (SDS). The stoichiometry of the intermediate is Fe(H(2)DFB)(phen)(2+) on the basis of a Schwarzenbach analysis of spectrophotometric data obtained at variable pH and phen concentrations. The ternary complex formation constant for the reaction FeHDFB(+) + H(+) + phen right arrow over left arrow Fe(H(2)DFB)(phen)(2+) is log K = 6.96 in aqueous solution and log K = 8.64 in aqueous 0.16 M SDS. The enhanced stability of Fe(H(2)DFB)(phen)(2+) in micellar solution was analyzed in terms of the pseudophase ion-exchange (PPIE) model of micellar reactions. The association constants for the binding of each reactant to the micellar pseudophase were measured by ultrafiltration. According to PPIE model calculations, the enhanced stability of Fe(H(2)DFB)(phen)(2+) in micellar SDS arises from a proximity effect created by the high local concentrations of reactants in the micellar pseudophase. The calculations also indicate that an inhibitory medium or compartmentalization effect is operative since the observed micellar enhancement is much smaller than predicted by the PPIE model. The micellar stabilization of the Fe(H(2)DFB)(phen)(2+) intermediate and the overall conversion of FeHDFB(+) to Fe(phen)(3)(2+) are discussed as a possible model system for siderophore iron release in microbial organisms.

Antioxidant activity of the monoamine oxidase B inhibitor lazabemide.

Free radical-induced damage to lipid and protein constituents of neuronal membranes contributes to the pathophysiology of neurodegenerative diseases, including Alzheimer's disease (AD). The development of an effective inhibitor of oxidative stress represents an important goal for the treatment of AD. In this study, the intrinsic antioxidant activity of lazabemide, a potent and reversible inhibitor of monoamine oxidase B (MAO-B), was tested in a membrane-based model of oxidative stress. Under physiologic-like conditions, lazabemide inhibited lipid peroxidation in a highly concentration-dependent manner. At low, pharmacologic levels of lazabemide (100.0 nM), there was a significant (P < 0.001) and catalytic reduction in lipid peroxide formation, as compared with control samples. The antioxidant activity of lazabemide was significantly more effective than that of either vitamin E or the MAO-B inhibitor, selegiline. The ability of lazabemide to inhibit oxidative damage is attributed to physico-chemical interactions with the membrane lipid bilayer, as determined by small angle x-ray diffraction methods. By partitioning into the membrane hydrocarbon core, lazabemide can inhibit the propagation of free radicals by electron-donating and resonance-stabilization mechanisms. These findings indicate that lazabemide is a potent and concentration-dependent inhibitor of membrane oxy-radical damage as a result of inhibiting membrane lipid peroxidation, independent of MAO-B interactions.

Membrane antioxidant effects of the charged dihydropyridine calcium antagonist amlodipine.

The effect of the highly lipophilic calcium channel antagonist (CCA) amlodipine on membrane oxyradical damage was examined and compared to that of other CCA analogs and a sulfhydryl-containing ACE inhibitor in isolated membrane vesicles enriched with polyunsaturated fatty acids (PUFA). Under physiological-like conditions, the dihydropyridine CCA amlodipine significantly (P<0.001) inhibited lipid peroxide formation (>10(2) microM) at concentrations as low as 10.0 nM. Under identical conditions, inhibition of lipid peroxide formation was not observed with representative CCA analogs (felodipine, verapamil, diltiazem) or the ACE inhibitor, captopril, at concentrations as high as 1.0 microM. The potent antioxidant activity of amlodipine is attributed to distinct membrane physico-chemical interactions. High-resolution differential scanning calorimetry showed that amlodipine effected marked changes in membrane thermodynamic properties as compared to other CCA analogs, including a marked reduction in the thermal phase transition temperature (-2.6 degrees C), enthalpy (-4.8 J/g) and cooperative unit size (-59%), relative to control samples. These findings indicate that the chemical structure of amlodipine contributes to distinct membrane biophysical interactions that lead to potent lipid antioxidant effects, independent of calcium channel modulation. These findings provide insights into potential new mechanisms of action for the charged CCA amlodipine.