Publications (4)7.89 Total impact
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Article: Equilibrium and structural characterization of ofloxacin-cyclodextrin complexation
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ABSTRACT: The enantiomer-specific characterization of ofloxacin–cyclodextrin complexes was carried out by a set of complementary analytical techniques. The apparent stability constants of the ofloxacin enantiomers with 20 different cyclodextrins at two different pH values were determined to achieve good resolution capillary electrophoresis enantioseparation either to establish enantioselective drug analysis assay, or to interpret and design improved host–guest interactions at the molecular level. The cyclodextrins studied differed in the nature of substituents, degree of substitution (DS), charge and purity, allowing a systematic test of these properties on the complexation. The seven-membered beta-cyclodextrin and its derivatives were found to be the most suitable hosts. Highest stability and best enantioseparation were observed for the carboxymethylated-beta-cyclodextrin (DS ~ 3.5). The effect of substitution pattern (SP) was investigated by molecular modeling, verifying that SP greatly affects the complex stability. Induced circular dichroism was observed and found especially significant on carboxymethylatedbeta-cyclodextrin. The complex stoichiometry and the geometry of the inclusion complexes were determined by 1H NMR spectroscopy, including 2D ROESY techniques. Irrespective of the kind of cyclodextrin, the complexation ratio was found to be 1:1. The alfa-cyclodextrin cavity can accommodate the oxazine ring only, whereas the whole tricyclic moiety can enter the beta- and gamma-cyclodextrin cavities. These equilibrium and structural information offer molecular basis for improved drug formulation.Journal of inclusion phenomena and macrocyclic chemistry 08/2012; · 1.17 Impact Factor -
Article: Solution-state NMR spectroscopy of famotidine revisited: spectral assignment, protonation sites, and their structural consequences.
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ABSTRACT: Multinuclear one (1D-) and two-dimensional (2D) nuclear magnetic resonance (NMR) spectroscopic investigations of famotidine, the most potent and widely used histamine H(2)-receptor antagonist, were carried out in dimethyl sulfoxide-d(6) (DMSO-d(6)) and water. Previous NMR assignments were either incomplete or full assignment was based only on 1D spectra and quantum-chemical calculations. Our work revealed several literature misassignments of the (1)H, (13)C, and (15)N NMR signals and clarified the acid-base properties of the compound at the site-specific level. The erroneous assignment of Baranska et al. (J. Mol. Struct. 2001, 563) probably originates from an incorrect hypothesis about the major conformation of famotidine in DMSO-d(6). A folded conformation similar to that observed in the solid-state was also assumed in solution, stabilized by an intramolecular hydrogen bond involving one of the sulphonamide NH(2) protons and the thiazole nitrogen. Our detailed 1D and 2D NMR experiments enabled complete ab initio (1)H, (13)C, and (15)N assignments and disproved the existence of the sulphonamide NH hydrogen bond in the major conformer. Rather, the molecule is predominantly present in an extended conformation in DMSO-d(6). The aqueous acid-base properties of famotidine were studied by 1D (1)H- and 2D (1)H/(13)C heteronuclear multiple-bond correlation (HMBC) NMR-pH titrations. The experiments identified its basic centers including a new protonation step at highly acidic conditions, which was also confirmed by titrations and quantum-chemical calculations on a model compound, 2-[4-(sulfanylmethyl)-1,3-thiazol-2-yl]guanidine. Famotidine is now proved to have four protonation steps in the following basicity order: the sulfonamidate anion protonates at pH = 11.3, followed by the protonation of the guanidine group at pH = 6.8, whereas, in strong acidic solutions, two overlapping protonation processes occur involving the amidine and thiazole moieties.Analytical and Bioanalytical Chemistry 12/2011; 402(4):1653-66. · 3.78 Impact Factor -
Article: Theoretical Conformational Analysis for Codeinone-6-oximes in Gas Phase and in Solution
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ABSTRACT: The Z/E isomer ratios for codeinone-6-oxime and 7,8-dihydro-codeinone-6-oxime in chloroform and in a water:acetonitrile 85:15 (volume ratio) mixture have been theoretically calculated using the polarizable continuum method at the B3LYP/6-31G* level. Gas phase optimized geometries and thermal corrections were used for obtaining total relative free energies in solution. For validating the B3LYP/6-31G* calculations, optimized geometries and relative energies for the gas phase formaldoxime have been compared with values from B3LYP/6-311++G** calculations. B3LYP/6-31G* optimized geometric parameters are almost constant for formaldoxime, the C-ring model compound, (methoxy-methyl)vinyl-ketone oxime, and codeinone oximes in the absence of special structural features. Transition states, one for each, have been identified for the syn−anti and anti−anti transformations of formaldoxime. The energy and free energy of the barrier for the syn to anti rotation are 9.4 and 8.5 kcal/mol, respectively; the corresponding barrier values for the anti−anti isomerization were calculated at 55.1 and 53.7 kcal/mol. The Onsager approach of the solvent effect breaks down for such large systems as codeinone oximes. Using the self-consistent ab initio PCM approach, the smallest solvent effect has been calculated just for the molecule with the largest dipole moment. Polarization energies for codeinone-6-oximes are larger than those of the 7,8-dihydro derivatives. The larger polarization energies are accompanied with more negative solute−solvent interaction energies in both solvents. Isomer/conformer compositions have been calculated on the basis of relative internal free energies and free energies of solvation. The frequency-dependent relative thermal correction is negligible for the anti-codeinone oximes, but the value is 0.66 kcal/mol for the Z/syn relative to the Z/anti conformer. In chloroform, the Z:E composition was calculated at 47.5:52.5 as compared to our experimental value of 69:31 from NMR measurements. In the water:acetonitrile mixture, the theoretical ratio is 65.7:34.3 as compared to 73:27 as determined by high-performance liquid chromatography. For 7,8-dihydro-codeinone-6-oxime, the calculated composition in chloroform is 92.4% E and 7.6% Z, and the theoretical values in the water/acetonitrile mixture are 93.9% E and 6.1% Z. Both predictions are close to the experimental finding that the E form is practically the only existing isomer in solution. The different Z/E relative stabilities for the codeinone-6-oxime and the 7,8-dihydro derivative are primarily attributed to a remarkable change in the geometry of the C-ring. Overall, PCM/B3LYP/6-31G* calculations can provide isomer/conformer equilibrium compositions in both nonpolar and aqueous solutions in fair agreement with experimental values.The Journal of Physical Chemistry A 08/2003; 107(39):7861-68. · 2.95 Impact Factor -
Article: Biomolekulák mikrospeciációja = Microspeciation and Biomolecules
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ABSTRACT: Biomolekulák mikrospeciációja Az élő világ sokféleségének egyik oka, hogy ugyanazon molekula többféle töltéssel és szerkezettel (azaz mikrorészecske, mikrospecies formájában) fordulhat elő és vehet részt az egyes kémiai és biokémiai folyamatokban, változatos reakciótermékeket eredményezve. E nanosecundum egyedi élettartamú, egymásba folytonosan átalakuló, ezért elválaszthatatlan, csak közvetett módszerekkel vizsgálható részecskék koncentrációjának és tulajdonságainak meghatározásában (mikrospeciációjában) - többek közt - megvalósítottuk: Új típusú, az irodalomban le nem írt mikroszkópikus fizikai-kémiai mennyiségek bevezetését (rotamer-specifikus megoszlási hányados, észter hidrolízis sebességi mikroállandó) Élettani vagy gyógyszertani jelentőségű molekulák jellemzését részecske-specifikus paraméterekkel (stressz elleni glutation, magzatvédő fólsav, tumorgátló metotrexát és imatinib, köhögéscsillapító folkodin, penicillin és kefalosporin antibiotikumok, gyulladásgátló tenoxikám, stb.) A mikro- és szubmikro speciáció körébe tartozó elvi kérdések tisztázását (mikroállandók és rotamer populációk NMR-alapú meghatározásának kritikai értékelése, az első irodalmi négycsoportos mikrospeciáció, a hisztamin biológiai kémiája). Eredményeink világszínvonalú nemzetközi folyóiratokban kaptak nyilvánosságot (J. Med. Chem., J. Phys. Chem. B, Anal. Bioanal. Chem., Eur. J. Pharm, Electrophoresis, stb.) | MICROSPECIATION OF BIOMOLECULES The chemical and biological diversity of the world stems partly from the fact that the molecules - especially the bio- and drug molecules - occur and react in various forms of protonation and conformation (i.e. microspecies), resulting in a cornucopia of products. Microspecies are of nanoseconds individual lifetime, which makes them inseparable, coexisting ones. In the research of their analytical determination and physicochemical characterization (i.e. microspeciation) our results include: Introduction and determination of previously undefined microscopic physicochemical quantities (rotamer-specific partition coefficient, microscopic rate constants of ester hydrolysis) Characterization of bio- and drug molecules in terms of species-specific parameters (anti-stress glutathione, fetus-protective folic acid, anti-cancer methotrexate and imatinib, anti inflammatory tenoxicame, penicilline and cephalosporine antibiotics, glutamate receptor ligand NMDA, etc.) Elucidation of some principal questions concerning microspeciation (critical reviews on NMR methods to evaluate microconstants and rotamer populations, microscopic characterization of a tetradentate ligand for the first time, the biological chemistry of histamine) Our results appeared in world-class journals of the field (J. Med. Chem., J. Phys. Chem. B, Anal. Bioanal. Chem., Eur. J. Pharm, Electrophoresis, etc.)
