Olga H. Hankovszky

Direct evidence for in vivo nitroxide free radical production from a new antiarrhythmic drug by epr spectroscopy

The new Class I anti-arrhythmic agent 2,2,5,5-tetramethyl-3-pyrroline-1-carboxamide derivative, is currently being evaluated in clinical trials in patients with a high risk for cardiac arrhythmias. In this study we show that this antiarrhythmic drug can be chemically converted to the nitroxide free radical analog. Further, using an in vivo Electron Paramagnetic Resonance (EPR) spectroscopy model by detecting free radicals in the distal portion of the tail of an anesthetized mouse, we demonstrate that the drug is oxidized to the corresponding nitroxide. In vitro studies using Chinese hamster V79 cells suggest that the oxidation products of the drug, namely, the hydroxylamine and the nitroxide protect against oxidative damage induced by hydrogen peroxide (H2O2). Taken together, our results suggest that, in addition to the antiarrhythmic effects of the parent drug, sufficient levels of nitroxides may accumulate from the parent drug in vivo to provide antioxidant defense to cardiac tissue that may be subject to ischemia and oxidation-driven injury.

pKa Values and Partition Coefficients of Nitroxide Spin Probes for Membrane Bioenergetics Measurements

Knowledge of pKas is necessary to calculate intracellular/intravesicular pH values from nitroxide accumulation in cells or vesicles as detected with electron spin resonance (ESR) spectroscopy. pKa values were confirmed in lipid vesicles of known internal pH. To help select probes that do not accumulate in lipid membranes, octanol/buffer partition coefficients of uncharged nitroxides were determined. As an application of selected probes, pH gradients and internal aqueous volumes were analyzed in mitochondria (one internal compartment) and in the cyanobacterium Synechococcus 6311 (two internal compartments). The combination of 3-carboxy-, 3-amino- and 3-aminocarbonyl-2,2,5,5-tetramethylpyrrolidin-1-yloxyl was found to be most satisfactory for determinations of internal pH and volumes.

SYNTHESIS AND STUDY OF DOUBLE (EPR ACTIVE AND FLUORESCENT) CHEMOSENSORS IN THE PRESENCE OF Fe3+ ION

The fluorescence properties of 4-aminophthalimide derivatives are influenced by the side-chain attached to the paramagnetic ring or its diamagnetic precursor. PET (photoinduced electron transfer)-induced fluorescence enhancement in the presence of Fe3+ ions was observed only in the case of diamagnetic basic side chain derivatives, since transient metal ions are present in biological systems, only double sensors lacking the above sensitivity are considered as potential reactive oxygen probes.

Chemistry of Spin-Labeled Amino Acids and Peptides

The ESR spectrum of the nitroxide group will be affected by constraint in an oriented electric or magnetic field if the nitroxide moiety combined with a macromolecule is placed in such an environment.

Synthesis of 2-(2-Thienyl)benzimidazoles by the Reaction of 2-(Mercaptomethyl)benzimidazole With β-Electrophilic Esters

Abstract New 2-(2-di- and tetrahydrothienyl)benzimidazole compounds were prepared by the ring closure reactions of 2-(mercaptomethyl)benzimidazole1,2 (1) and α,β-unsaturated compounds activated with electron-withdrawing groups.

Structure of the tetra-azacyclotetradecadienes obtained from α,β-enones and ethylenediamine

The tetra-azacyclotetradecadiene obtained from ethylenediamine and benzylideneacetone has the cisoid structure (I) while that obtained from ethylenediamine monoperchlorate and mesityl oxide has the transoid structure (IV).

Reaction products from 4-phenylbut-3-yn-2-one and aliphatic diamines or 2-aminoethanethiol, and from 2-aminoethanethiol and some αβ-enones

4-Phenylbut-3-yne-2-one reacts with α,ω-diamino-ethane and -propane either by condensation or by conjugate addition, dependant on the reaction conditions, but cyclisation products were not obtained. 2-Aminoethanethiol reacts with this ynone by conjugate addition of the amino-group, with benzylideneacetone to give a tetrahydro-thiazepine, and with chalcone to give mono- or bis-conjugate addition products.

Synthesis and study of new paramagnetic and diamagnetic verapamil derivatives

New derivatives of verapamil (1) modified with nitroxides and their precursors were synthesized and screened for reactive oxygen species (ROS)-scavenging activities. The basic structure was modified by changing the nitrile group to an amide or the methyl substituent on tertiary nitrogen with nitroxides and their reduced forms (hydroxylamine and secondary amines). Among the new verapamil derivatives compound 16B [Mohan, I. K.; Kahn, M.; Wisel, S.; Selvendiran, K.; Sridhar, A.; Carnes, C.A.; Bognár, B.; Kálai, T.; Hideg, K.; Kuppusamy, P. Am. J. Physiol. Heart Circ. Physiol.2009, 296, 140], modified with hydroxylamine salt of 2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridine-1-yloxyl proved to be the best ROS scavenger in vitro and protected HSMC and CHO cells against H(2)O(2) induced damage.

Macrocyclic ligands with potential axial interactions. The preparation of copper(II), nickel(II) and cobalt(III) complexes of 7,14-o-hydroxyphenyl-5,12-dimethyl-1,4,8,11-tetraazacyclotetradeca-4,11-diene

SummaryThe new macrocyclic ligand 7,14-o-hydroxyphenyl-5,12-dimethyl-1,4,8,11-tetraazacyclotetradeca-4,11-diene (1=L) has been prepared and complexes with copper(II), nickel(II) and cobalt(III) characterised. The nickel(II) complex is a yellow square-planar species, while the purple-red copper(II) complex is probably tetragonal in both the solid state and solution. The complexes appear to have an N-meso arrangement of the chiral nitrogen centres with the HOC6H4 groups occupying equatorial sites so that axial interactions with the metal do not occur. A variety oftrans-[CoLX2]ClO4 complexes (X=Cl, Br, NO2, or N3) have been characterised.

Copper(II), nickel(II) and cobalt(III) complexes of the macrocyclic ligand C-meso-7,14-diphenyl-5,6-butano-12,13-butano-1,4,8,11-tetraazacyclotetradeca-4,11-diene

SummaryMetal complexes of the macrocyclic tetraaza ligand C-meso-7,14-diphenyl-5,6-butano-12,13-butano-1,4,8,11-tetraazacyclotetradeca-4,11-diene (L) are described. The copper(II) and nickel(II) complexes, isolated as their perchlorate salts, are 4-coordinate species. Several cobalt(III) complexes,trans-[CoLX2]+(X = Cl−, Br−, NO2− or N3− have also been characterised. The most probable stereochemistry of the ligand in the metal complexes is the C-meso-N-meso arrangements of the chiral centres. The N-meso stereochemistry leads to the bulky phenyl groups lying in equatorial positions. I.r. and d-d spectra are reported for the various complexes described.