105 research outputs found
Characterization of the Site‐Specific Acid‐Base Equilibria of 3‐Nitrotyrosine
The complete macro- and microequilibrium analyses of 3-nitrotyrosine, a biomarker of oxidative stressdamage, are presented for the first time. The protonation macroconstants were determined by1H-NMR-pHtitration, while microconstants were elucidated by a combination of deductive and NMR methods, in whichproperties of the methyl ester derivative as an auxiliary compound were also studied. Combination of the NMR-pH characterization of the title and auxiliary compounds and the pair-interactivity parameters of 3-iodotyrosineprovided the sufficient system to evaluate all the microconstants. NMR-pH profiles, macroscopic and microscopicprotonation schemes, and species-specific distribution diagrams are included. The phenolate basicity of 3-nitrotyrosine is 500 times below that of tyrosine, and it is even lower than that of 3-iodotyrosine. Thisphenomenon can be explained by the stronger electron withdrawing and the negative mesomeric effect of thenitro group. Based on our results, 89 % of the phenolic OH groups are deprotonated in 3-NT molecules at the pHof the blood plasma
Bio- és gyógyszermolekulák mikrospeciációja = Microspeciation of bio- and drug molecules
A kutatás csoportosított eredményei az alábbiak: 1) Új elvek és módszerek bio- és gyógyszermolekulák mikrospeciációjában 1)a) A mikroszkópikus lipofilitás meghatározása, különös tekintettel az ikerionos és töltésmentes protonáltsági izomerekre A hatóanyagok felszívódásában kulcsfontosságú mikroszkópikus lipofilitás jellemzéséhez levezettük a szükséges összefüggéseket és meghatároztuk konkrét értéküket több jelentős molekulára (morfin, tiroxin, nifluminsav, vinpocetin) 1)b) Torzításmentes, erősen lúgos oldatokban is használható, NMR alapú pH-meghatározási módszerkidolgozása és alkalmazása 2) Bio-, gyógyszer- és gyógyszerjelölt molekulák részecskéinek receptor-kötési vizsgálata in silico módszerekkel 3) Biomolekulák metabonomikai analízise 4) Biológiai alapmolekulák (szerotonin, tiroxin, arginin) mikrospeciációja 5) Néhány hatóanyag (cetirizin, famotidin, tolperizon, fluorokinolonok) mikrospeciációja 6) Bio- és gyógyszermolekulák ciklodextrin komplexeinek részecske-specifikus egyensúlyi és szerkezeti jellemzése 7) Új gyógyszerjelölt vegyületek szintézise és jellemzése 8) Összefoglaló közlemények megjelentetése a témakörben Ezen eredmények 31 közlemény és egy könyvrészlet formájában jelentek meg jelentős nemzetközi folyóiratokban ( J. Med. Chem, J. Proteom. Res, Anal. Bioanal. Chem, J. Pharm. Biomed. Anal., Eur, J. Pharm. Sci., Electrophoresis, Tetrahedron Letters, stb.) | Results of the funded research can be sorted as follows: 1) New principles and methods in the microspeciation of bio and drug molecules 1)a) Determination of microscopic lipophilicity, with special regard to the noncharged and zwitterionic protonation isomers. Physicochemical relationships of microscopic lipophilicity, the key parameter in pharmacokinetics have been deduced, and real microscopic lipophilicities have been determined for such important molecules as morphine, thyroxin, niflumic acid, vinpocetine. 1)b) Elaboration and application of an undistorted, NMR-based pH determination method that can be used in highly basic solutions too. 2) Receptor-binding studies on bio-, drug and drug candidate molecules, by in silico techniques. 3) Metabonomic analysis of biomolecules 4) Microspeciation of some fundamental biomolecules (serotonin, thyroxin, arginin) 5) Microspeciation of some therapeutic agents (cetirizin, famotidin, tolperizon, fluorokinolons9 6) Species-specific equilibrium and structural characterization of cyclodextrin complexation of bio- and drug molecules 7) Synthesis and characterization of new drug candidates 8) Publishing related review papers These results have been published as 31 papers and one book chapter in prestigious international journals, including J. Med. Chem., J. Proteome. Res, Anal. Bioanal. Chem, J. Pharm. Biomed. Anal., Eur, J. Pharm. Sci., Electrophoresis, Tetrahedron Letters
Correlation between the NMR Chemical Shifts and Thiolate Protonation Constants of Cysteamine, Homocysteine, and Penicillamine
1H and 13C NMR measurements were carried out to explore anticipated correlations between chemical shifts versus thiolate basicities and redox potentials of cysteamine, homocysteine, penicillamine, and their homodisulfides. All correlations were analyzed and statistically evaluated. The closest correlation was observed for the αCH nuclei concerning 1H and 13C NMR data. Since neither site-specific basicities nor site-specific redox potentials can be directly measured by any means in peptides and proteins containing several thiol and/or disulfide units, these data provide a simple method and predictive power to estimate the aforementioned site-specific physicochemical parameters for analogous sulfur-containing moieties in related biopolymers
Physicochemical Characterization and Cyclodextrin Complexation of the Anticancer Drug Lapatinib
Lapatinib (LAP), the tyrosine kinase inhibitor drug with moderate bioavailability, was characterized in terms of physicochemical properties: acid-base characteristics, lipophilicity, and solubility. The highly lipophilic nature of the drug and its extremely low water solubility (S0=0.82 nM) limit the development of a parenteral formulation. In order to enhance solubility and bioavailability, inclusion complex formation with cyclodextrins (CDs) is a promising method of choice. Therefore, LAP-CD interactions were also studied by a multianalytical approach. The stability constants of LAP with native cyclodextrins, determined by UV spectroscopy, identified the seven-membered β-CD as the most suitable host. Continuous variation method (Job’s plot) by 1H NMR showed a 1 : 1 stoichiometry for the complexes. The geometry of the complex was elucidated by 2D ROESY NMR measurements and molecular modeling, indicating that the partial molecular encapsulation includes the fluorophenyl ring of LAP. Phase-solubility studies with four CDs, β-CD, (2-hydroxypropyl)-β-cyclodextrin (HP-β-CD), randomly methylated-β- (RAMEB-) cyclodextrin, and sulfobutylether-β-cyclodextrin (SBE-β-CD), show an AL type diagram and highly increased solubility via CD complexation. The results are especially promising with SBE-β-CD, exerting more than 600-fold gain in solubility. The equilibrium and structural information presented herein can offer the molecular basis for an improved drug formulation with enhanced bioavailability
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