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1.
Magn Reson Chem ; 60(1): 148-156, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34273131

RESUMO

The 77 Se NMR spectra of selenate were studied under various circumstances, such as concentration, pH, temperature, ionic strength, and D2 O:H2 O ratio, in order to examine its potential as a water-soluble internal chemical shift standard. The performance of selenate as a chemical shift reference and that of other attempted ones from the literature (dimethyl selenide, tetramethylsilane/TMS, and 3-(trimethylsilyl)propane-1-sulfonate/DSS) was also explored. The uncertainty in the resulting chemical shift relative to the effective spectral width is comparable to that of DSS. Compared to the currently prevalent water-soluble external chemical shift reference, selenic acid solution, the properties of internal selenate are much more favorable in terms of ease of use. We have also demonstrated that selenate can be used in reducing media, which is inevitable for the analysis of selenol compounds. Thus, it can be stated that sodium selenate is a robust internal chemical shift reference in aqueous media for 77 Se NMR measurements; the chemical shift of this reference in a solution containing 5 V/V% D2 O at 25°C and 0.15 mol·dm-3 ionic strength is 1048.65 ppm relative to 60 V/V% dimethyl selenide in CDCl3 and 1046.40 ppm relative to the 1 H signal of 0.03 V/V% TMS in CDCl3 . In summary, a water-soluble, selenium-containing internal chemical shift reference compound was introduced for 77 Se NMR measurements for the first time in the literature, and with the aforementioned results all previous 77 Se measurements can be converted to a unified scale defined by the International Union of Pure and Applied Chemistry.

2.
Chem Biodivers ; 18(10): e2100464, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34467647

RESUMO

The reduced derivative of α-conotoxin MI, a 14 amino acid peptide is characterized by NMR-pH titrations and molecular dynamics simulations to determine the protonation constants of the nine basic moieties, including four cysteine thiolates, and the charge-dependent structural properties. The peptide conformation at various protonation states was determined. The results show that the disulfide motifs in the native globular α-conotoxin MI occur between those cysteine moieties that exhibit the most similar thiolate basicities. Since the basicity of thiolates correlates to its redox potential, this phenomenon can be explained by the higher reactivity of the two thiolates with higher basicities. The folding of the oxidized peptide is further facilitated by the loop-like structure of the reduced form, which brings the thiolate groups into sufficient proximity. The 9 group-specific protonation constants and the related, charge-dependent, species-specific peptide structures are presented.


Assuntos
Conotoxinas/química , Concentração de Íons de Hidrogênio , Estrutura Molecular , Oxirredução , Soluções
3.
Int J Mol Sci ; 22(8)2021 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-33918622

RESUMO

A comparative phytochemical study on the phenylethanoid glycoside (PhEG) composition of the underground organs of three Plantago species (P. lanceolata, P. major, and P. media) and that of the fruit wall and seed parts of Forsythia suspensa and F. europaea fruits was performed. The leaves of these Forsythia species and six cultivars of the hybrid F. × intermedia were also analyzed, demonstrating the tissue-specific accumulation and decomposition of PhEGs. Our analyses confirmed the significance of selected tissues as new and abundant sources of these valuable natural compounds. The optimized heat treatment of tissues containing high amounts of the PhEG plantamajoside (PM) or forsythoside A (FA), which was performed in distilled water, resulted in their characteristic isomerizations. In addition to PM and FA, high amounts of the isomerization products could also be isolated after heat treatment. The isomerization mechanisms were elucidated by molecular modeling, and the structures of PhEGs were identified by nuclear magnetic resonance spectroscopy (NMR) and high-resolution mass spectrometry (HR-MS) techniques, also confirming the possibility of discriminating regioisomeric PhEGs by tandem MS. The PhEGs showed no cytostatic activity in non-human primate Vero E6 cells, supporting their safe use as natural medicines and allowing their antiviral potency to be tested.


Assuntos
Forsythia/química , Glicosídeos/química , Compostos Fitoquímicos/química , Plantago/química , Animais , Chlorocebus aethiops , Cromatografia Líquida de Alta Pressão , Forsythia/metabolismo , Glicosídeos/metabolismo , Glicosídeos/farmacologia , Isomerismo , Conformação Molecular , Estrutura Molecular , Especificidade de Órgãos , Compostos Fitoquímicos/metabolismo , Compostos Fitoquímicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Plantago/metabolismo , Relação Estrutura-Atividade , Células Vero
4.
Chirality ; 32(2): 158-167, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31795019

RESUMO

A direct HPLC method was developed for the enantioseparation of pantoprazole using macrocyclic glycopeptide-based chiral stationary phases, along with various methods to determine the elution order without isolation of the individual enantiomers. In the preliminary screening, four macrocyclic glycopeptide-based chiral stationary phases containing vancomycin (Chirobiotic V), ristocetin A (Chirobiotic R), teicoplanin (Chirobiotic T), and teicoplanin-aglycone (Chirobiotic TAG) were screened in polar organic and reversed-phase mode. Best results were achieved by using Chirobiotic TAG column and a methanol-water mixture as mobile phase. Further method optimization was performed using a face-centered central composite design to achieve the highest chiral resolution. Optimized parameters, offering baseline separation (resolution = 1.91 ± 0.03) were as follows: Chirobiotic TAG stationary phase, thermostated at 10°C, mobile phase consisting of methanol/20mM ammonium acetate 60:40 v/v, and 0.6 mL/min flow rate. Enantiomer elution order was determined using HPLC hyphenated with circular dichroism (CD) spectroscopy detection. The online CD signals of the separated pantoprazole enantiomers at selected wavelengths were compared with the structurally analogous esomeprazole enantiomer. For further verification, the inline rapid, multiscan CD signals were compared with the quantum chemically calculated CD spectra. Furthermore, docking calculations were used to investigate the enantiorecognition at molecular level. The molecular docking shows that the R-enantiomer binds stronger to the chiral selector than its antipode, which is in accordance with the determined elution order on the column-S- followed by the R-isomer. Thus, combined methods, HPLC-CD and theoretical calculations, are highly efficient in predicting the elution order of enantiomers.

5.
Electrophoresis ; 40(15): 1897-1903, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30758065

RESUMO

Pressure-assisted stereospecific capillary electrophoresis method was developed for the determination of enantiomeric purity of the antiparkinsonian agent (R)-rasagiline. The optimized method, 50 mM glycine-HCl buffer pH 2, supplied with 30 mM sulfobutylether-ß-cyclodextrin, at 35°C, applying 12 kV in reversed polarity, and -8 mbar pressure (vacuum), short-end injection with -25 mbar × 2 s, was successful for baseline separation of rasagiline enantiomers (Rs = 3.5 ± 0.1) in a short analysis time. The method was validated according to current guidelines and proved to be reliable, linear, precise and accurate for determination of 0.15% S-enantiomer as chiral impurity in R-rasagiline sample, as well as quantification of the eutomer. Method application was tested on a commercial tablet formulation. Determination of spatial structure of diastereomeric associates was based on 1 H and 2D ROESY NMR, indicating that the aromatic moiety of the molecule can enter the cyclodextrin cavity. NMR titration and molecular modeling revealed that S-rasagiline formed a more stable inclusion complex with sulfobutylether-ß-cyclodextrin, than its antipode, which is in agreement with electrophoretic results.


Assuntos
Eletroforese Capilar/métodos , Indanos , Espectroscopia de Ressonância Magnética/métodos , Modelos Moleculares , beta-Ciclodextrinas/química , Indanos/análise , Indanos/química , Indanos/isolamento & purificação , Limite de Detecção , Modelos Lineares , Reprodutibilidade dos Testes , Estereoisomerismo
6.
Electrophoresis ; 40(21): 2799-2805, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31281995

RESUMO

Novel capillary electrophoresis methods using CDs as chiral selectors were developed and validated for the chiral separation of lansoprazole and rabeprazole, two proton pump inhibitors. Fourteen different neutral and anionic CDs were screened at pH 4 and 7 in the preliminary analysis. Sulfobutyl-ether-ß-CD with a degree of substitution of 6.5 and 10 at neutral pH proved to be the most suitable chiral selector for both compounds. Various dual CD systems were also compared, and the possible mechanisms of enantiomer separation were investigated. A dual selector system containing sulfobutyl-ether-ß-CD degree of substitution 6.5 and native γ-CD proved to be the most adequate system for the separations. Method optimization was carried out using an experimental design approach, performing an initial fractional factorial screening design, followed by a central composite design to establish the optimal analytical conditions. The optimized methods (25 mM phosphate buffer, pH 7, 10 mM sulfobutyl-ether-ß-CD/20 mM γ-CD, +20 kV voltage; 17°C temperature; 50 mbar/3 s injection, detection at 210 nm for lansoprazole; 25 mM phosphate buffer, pH 7, 15 mM sulfobutyl-ether-ß-CD/30 mM γ-CD, +20 kV voltage; 18°C temperature; 50 mbar/3 s injection, detection at 210 nm for rabeprazole) provided baseline separation for lansoprazole (Rs = 2.91) and rabeprazole (Rs = 2.53) enantiomers with favorable migration order (in both cases the S-enantiomers migrates first). The optimized methods were validated according to current guidelines and proved to be reliable, linear, precise, and accurate for the determination of 0.15% distomer as chiral impurity in dexlansoprazole and dexrabeprazole samples.


Assuntos
Ciclodextrinas/química , Eletroforese Capilar/métodos , Lansoprazol/análise , Rabeprazol/análise , Lansoprazol/química , Lansoprazol/isolamento & purificação , Limite de Detecção , Modelos Lineares , Rabeprazol/química , Rabeprazol/isolamento & purificação , Reprodutibilidade dos Testes , Estereoisomerismo
7.
Chem Biodivers ; 16(9): e1900358, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31364276

RESUMO

The complete macro- and microequilibrium analyses of 3-nitrotyrosine, a biomarker of oxidative stress damage, are presented for the first time. The protonation macroconstants were determined by 1 H-NMR-pH titration, while microconstants were elucidated by a combination of deductive and NMR methods, in which properties 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-iodotyrosine provided the sufficient system to evaluate all the microconstants. NMR-pH profiles, macroscopic and microscopic protonation 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. This phenomenon can be explained by the stronger electron withdrawing and the negative mesomeric effect of the nitro group. Based on our results, 89 % of the phenolic OH groups are deprotonated in 3-NT molecules at the pH of the blood plasma.


Assuntos
Tirosina/análogos & derivados , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Tirosina/análise
8.
AAPS PharmSciTech ; 20(8): 314, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31529175

RESUMO

Baicalin is a flavone glycoside extracted from Scutellaria baicalensis, a traditional Chinese herbal medicine. Numerous pharmacological effects of baicalin were reported (e.g. antioxidant, anxiolytic); nevertheless, the most important physicochemical properties influencing the pharmacokinetic behaviour and the concomitant oral bioavailability have not yet been described in a comprehensive study. The aim of this project was to characterize the acid-base, lipophilicity, biorelevant solubility and permeability properties of the drug substance and providing scientific data to support the dosage form design. Another important objective was the comparative evaluation of six various baicalin-cyclodextrin (CD) inclusion complexes along with the creation of a suitable Drug Delivery System (DDS) for this BCS IV drug. Biorelevant profiling was carried out by NMR-pH titrations, saturation shake-flask and distribution coefficients (logP) measurements, while CD inclusion studies were fulfilled by experimental methods (phase solubility, 1H/13C NMR, 2D ROESY) and computational approaches. Due to low aqueous solubility (67.03 ± 1.60 µg/ml) and low permeability (Papp = 0.037 × 10-6 cm/s), baicalin is classified as BCS IV. The γ-CD complexation significantly increased the solubility of baicalin (~ 5 times). The most promoted chemical shift change occurred in baicalin-γ-CD complex. Computational studies showed disparate binding pattern for baicalin in case of ß- and γ-CD; furthermore, the calculated complexation energy was - 162.4 kJ mol-1 for ß-CD, while it was significantly stronger for γ-CD (- 181.5 kJ mol-1). The physicochemical and structural information of baicalin and its CD complexes introduced herein can create molecular basis for a promising DDS with enhanced bioavailability containing a bioactive phytopharmacon.


Assuntos
Antineoplásicos Fitogênicos/química , Ciclodextrinas/química , Flavonoides/química , Antineoplásicos Fitogênicos/administração & dosagem , Disponibilidade Biológica , Sistemas de Liberação de Medicamentos , Flavonoides/administração & dosagem , Lipídeos/química , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Permeabilidade , Solubilidade , Termodinâmica
9.
Anal Chem ; 90(20): 12075-12080, 2018 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-30199237

RESUMO

A novel method was elaborated, and a set of 1H NMR-pH indicator molecules was selected to develop an NMR-based pH determination method, which does not need any glass or other electrodes or any separate reference compound, being thus devoid of the usual acid and base errors of the glass and combined electrodes. The method utilizes organic compounds of accurately known basicity and two or more carbon-bound protons, whose chemical shifts respond differently to pH changes. Accurate determination of protonation constants in pH extrema was achieved by the method of relative basicities using compounds of sequentially incremented protonation constants. The entire pH scale can be covered by six indicator molecules. The method was developed for two ionic strengths, 1.00 and 0.15 M.

10.
Chirality ; 30(1): 95-105, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29024201

RESUMO

Enantioseparation of the antidiarrheal drug, racecadotril, was investigated by liquid chromatography using polysaccharide-type chiral stationary phases in polar organic mode. The enantiodiscrimininating properties of 4 different chiral columns (Chiralpak AD, Chiralcel OD, Chiralpak AS, Chiralcel OJ) with 5 different solvents (methanol, ethanol, 1-propanol, 2-propanol, and acetonitrile) at 5 different temperatures (5-40 °C) were investigated. Apart from Chiralpak AS column the other 3 columns showed significant enantioseparation capabilities. Among the tested mobile phases, alcohol type solvents were superior over acetonitrile, and significant differences in enantioselective performance of the selector were observed depending on the type of alcohol employed. Van't Hoff analysis was used for calculation of thermodynamic parameters which revealed that enantioseparation is mainly enthalpy controlled; however, enthropic control was also observed. Enantiopure standard was used to determine the enantiomer elution order, revealing chiral selector-and mobile-phase dependent reversal of enantiomer elution order. Using the optimized method (Chiralcel OJ stationary phase, thermostated at 10 °C, 100% methanol, flow rate: 0.6 mL/min) baseline separation of racecadotril enantiomers (resolution = 3.00 ± 0.02) was achieved, with the R-enantiomer eluting first. The method was validated according to the ICH guidelines, and its application was tested on capsule and granules containing the racemic mixture of the drug.


Assuntos
2-Propanol/química , Amilose/análogos & derivados , Carbamatos/química , Fenilcarbamatos/química , Polissacarídeos/química , Tiorfano/análogos & derivados , Amilose/química , Cromatografia Líquida de Alta Pressão , Estrutura Molecular , Solventes , Estereoisomerismo , Termodinâmica , Tiorfano/química
11.
J Sep Sci ; 41(6): 1414-1423, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29211341

RESUMO

Complementary techniques were applied for the investigation of the chiral recognition and enantiomeric resolution of lenalidomide using various cyclodextrins and polysaccharides as chiral selectors. The high-performance liquid chromatography enantioseparation of the anticancer drug was achieved using polysaccharide-type chiral stationary phases in polar organic mode. Elution order and absolute configuration were elucidated by combined circular dichroism spectroscopy and time-dependent density functional theory calculations after the isolation of pure enantiomers. Chiral selector dependent and mobile-phase dependent reversal of the enantiomer elution order was observed, and the nonracemic nature of the lenalidomide sample was also demonstrated. Eight anionic cyclodextrins were screened for their ability to discriminate between the uncharged enantiomers by using capillary electrophoresis. Only two derivatives presented chiral interactions, these cases being interpreted in terms of apparent stability constants and complex mobilities. The best results were delivered by sulfobutylether-ß-cyclodextrin, where quasi-equal stability constants were recorded and the enantiodiscrimination process was mainly driven by different mobilities of the transient diastereomeric complexes. The optimized high-performance liquid chromatography (Chiralcel OJ column, pure ethanol with 0.6 mL/min flow rate, 40°C) and capillary electrophoresis methods (30 mM sulfobutylether-ß-cyclodextrin, 30 mM phosphate pH 6.5, 12 kV applied voltage, 10°C) were validated for the determination of 0.1% (R)-lenalidomide as a chiral impurity, which could be important if a racemic switch is achieved.


Assuntos
Ciclodextrinas/química , Polissacarídeos/química , Talidomida/análogos & derivados , Cromatografia Líquida de Alta Pressão , Eletroforese Capilar , Lenalidomida , Estrutura Molecular , Teoria Quântica , Talidomida/química , Talidomida/isolamento & purificação
12.
Electrophoresis ; 38(15): 1886-1894, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28221678

RESUMO

The enantiomers of praziquantel, the drug of choice in schistosomiasis, were separated by electrokinetic chromatography with cyclodextrins. Nine anionic cyclodextrins were screened for their ability to discriminate between the uncharged enantiomers. Seven investigated selectors presented chiral interactions with the enantiomers, these cases being interpreted in terms of stability constants and complex mobilities. The best results were delivered by sulfated-ß-cyclodextrin, where quasi-equal stability constants were accompanied by extreme selectivity values and was explained on the basis of highly different mobilities of the transient diastereomeric complexes. Since the enantiomer migration order was unfavorable, a simple polarity switch was employed (detection end at anode), which apart from migration order reversal, also resulted in extreme resolution values (Rs > 35) and increased migration times. After optimization (50 mM phosphate buffer pH 2.0, supplied with 15 mM sulfated-ß-cyclodextrin, 15 kV, capillary temperature 25°C, short-end injection with 50 mbar × 2 s), analysis time under 10 min were obtained, while still maintaining high resolution (Rs > 10). The method was validated according to the ICH guidelines and application of the method was tested on in-house synthetized R-praziquantel batches and on commercial, combination tablets containing racemic mixture of the drug.


Assuntos
Eletroforese Capilar/métodos , Praziquantel/química , Praziquantel/isolamento & purificação , Limite de Detecção , Modelos Lineares , Praziquantel/análise , Praziquantel/normas , Reprodutibilidade dos Testes , Estereoisomerismo
13.
Chem Biodivers ; 14(8)2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28502117

RESUMO

Species-specific partition coefficients in the octanol/water system were determined for the neurotransmitter serotonin (5-HT) and its precursor 5-hydroxytryptophan (5-HTP). The pH-independent partition coefficients (p) of the individual microspecies were determined by combination of experimentally measured distribution constants and a custom-tailored evaluation method, using highly similar auxiliary compounds. Experimental microscopic partition coefficients for triprotic molecules have only been reported before for thyroxine and its derivatives. The parabolic pH-distribution profile of 5-HT shows the dominance of the lipophilic non-charged microspecies, with a log p of 0.66. However, the most lipophilic non-charged form of 5-HTP, with a log p of 0.31, has no significant contribution to the distribution coefficient at any pH value. Instead, the less lipophilic zwitterionic protonation isomer dominates the distribution in the pH range 2.10 - 11.11. Although the non-charged microspecies of 5-HTP is 151 times more lipophilic than its zwitterionic protonation isomer, the overwhelming dominance of the zwitterionic form ensures that its contribution to the overall lipophilicity exceeds 1320 times that of the non-charged one. This fact is another counter-example of the widespread belief that passive diffusion into lipophilic media is predominated by the non-charged species. The lipophilicity profile of 5-HT and 5-HTP is depicted in terms of species-specific lipophilicities.


Assuntos
5-Hidroxitriptofano/química , Serotonina/química , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Íons/química , Isomerismo , Espectrofotometria Ultravioleta
14.
Chirality ; 28(3): 199-203, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26708721

RESUMO

The racemic mixture of pomalidomide (POM), a second-generation immunomodulatory uncharged drug, was separated into enantiomers by capillary zone electrophoresis for the first time. Seven different chargeable cyclodextrin (CD) derivatives were screened as complexing agents and chiral selectors, investigating the stability of the POM-CD inclusion complexes and their enantiodiscriminating capacities. Based on preliminary experiments, carboxymethyl-ß-CD (CM-ß-CD) was found to be the most effective chiral selector. Factors influencing enantioseparation were systematically optimized, using an orthogonal experimental design. Optimal parameters (background electrolyte [BGE]: 50 mM Tris-acetate buffer, pH 6.5, containing 15 mM CM-ß-CD; capillary temperature: 20°C; voltage applied +15 kV) allowed baseline separation of POM enantiomers with a resolution as high as 4.87. The developed method was validated, in terms of sensitivity (limit of detection and limit of quantification), linearity, accuracy, repeatability, and intermediate precision.


Assuntos
Ciclodextrinas/química , Talidomida/análogos & derivados , beta-Ciclodextrinas/química , Eletroforese Capilar , Concentração de Íons de Hidrogênio , Estereoisomerismo , Talidomida/química
15.
J Sep Sci ; 39(15): 2941-9, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27279456

RESUMO

A sensitive and validated liquid chromatography with mass spectrometry method was developed for the enantioseparation of the racemic mixture of pomalidomide, a novel, second-generation immunomodulatory drug, using ß-cyclodextrin-bonded stationary phases. Four cyclodextrin columns (ß-, hydroxypropyl-ß-, carboxymethyl-ß-, and sulfobutyl-ß-cyclodextrin) were screened and the effects of eluent composition, flow rate, temperature, and organic modifier on enantioseparation were studied. Optimized parameters, offering baseline separation (resolution = 2.70 ± 0.02) were the following: ß-cyclodextrin stationary phase, thermostatted at 15°C, and mobile phase consisting of methanol/0.1% acetic acid 10:90 v/v, delivered with 0.8 mL/min flow rate. For the optimized parameter at multiple reaction monitoring mode 274.1-201.0 transition with 20 eV collision energy and 100 V fragmentor voltage the limit of detection and limit of quantitation were 0.75 and 2.00 ng/mL, respectively. Since enantiopure standards were not available, elution order was determined upon comparison of the circular dichroism signals of the separated pomalidomide enantiomers with that of enantiopure thalidomide. The mechanisms underlying the chiral discrimination between the enantiomers were also investigated. Pomalidomide-ß-cyclodextrin inclusion complex was characterized using nuclear magnetic resonance spectroscopy and molecular modeling. The thermodynamic aspects of chiral separation were also studied.


Assuntos
Ciclodextrinas/química , Talidomida/análogos & derivados , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Modelos Moleculares , Estrutura Molecular , Estereoisomerismo , Talidomida/química , Talidomida/isolamento & purificação
16.
Biomed Chromatogr ; 30(6): 923-32, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-26433204

RESUMO

In this study the polyphenolic composition of lilac flowers and fruits was determined for the first time. For the identification of compounds, accurate molecular masses and formulas, acquired by LC and ESI-TOF-MS and fragmentation pattern given by LC-ESI/MS/MS analyses, were used. Our chromatographic system in conjunction with tandem MS was found to be valuable in the rapid separation and determination of the multiple constituents in methanolic extracts of lilac flowers and fruits. Altogether 34 phenolics, comprising 18 secoiridoids, seven phenylpropanoids, four flavonoids and five low-molecular-weight phenols, were identified. As marker compounds two secoiridoids (oleuropein and nuzhenide), two phenylpropanoids (acteoside and echinacoside) and rutin were quantified by validated methods. As a result of quantitative analysis, it was confirmed that flowers contain significant amounts of phenylpropanoids (acteoside, 2.48%; echinacoside, 0.75%) and oleuropein (0.95%), while in fruits secoiridoid oleuropein (1.09%) and nuzhenide (0.42%) are the major secondary metabolites. The radical scavenging activities of the extracts and the constituents were investigated by DPPH (2,2-diphenyl-1-picrylhydrazyl) and ABTS [2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid)] assays. Both extracts show remarkable antioxidant activities. Our results clearly show that lilac flowers and fruits are inexpensive, readily available natural sources of phenolic compounds with pharmacological and cosmetic applications. Copyright © 2015 John Wiley & Sons, Ltd.


Assuntos
Antioxidantes/química , Cromatografia Líquida de Alta Pressão/métodos , Flores/química , Fenóis/química , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrofotometria Ultravioleta/métodos , Syringa/química
17.
Chem Biodivers ; 13(7): 861-9, 2016 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-27272749

RESUMO

Lipoic acid, the biomolecule of vital importance following glycolysis, shows diversity in its thiol/disulfide equilibria and also in its eight different protonation forms of the reduced molecule. In this paper, lipoic acid, lipoamide, and their dihydro derivatives were studied to quantify their solubility, acid-base, and lipophilicity properties at a submolecular level. The acid-base properties are characterized in terms of six macroscopic, 12 microscopic protonation constants, and three interactivity parameters. The species-specific basicities, the pH-dependent distribution of the microspecies, and lipophilicity parameters are interpreted by various intramolecular effects, and contribute to understanding the antioxidant, chelate-forming, and enzyme cofactor behavior of the molecules observed.


Assuntos
Antioxidantes/química , Ácido Tióctico/química , Físico-Química , Concentração de Íons de Hidrogênio , Conformação Molecular , Solubilidade , Termodinâmica
18.
Acta Pharm Hung ; 85(4): 123-9, 2015.
Artigo em Húngaro | MEDLINE | ID: mdl-26964400

RESUMO

Resveratrol is a polyphenol that can be found in various plants, including grapes. Wines therefore also contain this compound. The famous phenomenon, named "French paradox" is considered to be an effect of resveratrol: the regular, modest consumption of red wine causes low incidence of cardiovascular diseases. Resveratrol is also reported to have anti-carcinogenic, anti-inflammatory, neuroprotective, and several further beneficial effects. As yet, resveratrol is not a registered drug in Hungary; nevertheless it is a common food supplement. Paradoxically, this is the very danger of its use: it can have harmful side-effects with several drugs. The bioavailability of resveratrol is, however, not favorable, due to its poor water-solubility and extensive metabolism. Our current knowledge is still far from being sufficient to understand its mode of action at a molecular level. Only a few of the most important physicochemical properties has been determined so far. The two major directions of pharmaceutical research of resveratrol are the elaboration of formulation systems that can improve the water solubility; the other is the development of analogous agents of enhanced effects.


Assuntos
Estilbenos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Anticarcinógenos/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Antioxidantes/farmacologia , Glicemia/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Química Farmacêutica , Suplementos Nutricionais , Humanos , Hungria , Obesidade/tratamento farmacológico , Obesidade/prevenção & controle , Resveratrol , Solubilidade , Estilbenos/química , Estilbenos/farmacocinética
19.
Anal Bioanal Chem ; 406(9-10): 2377-87, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24510213

RESUMO

Ovothiol A, a small biomolecule with highly potent antioxidant capacity, and three newly synthesized derivatives were studied by (1)H NMR, (15)N NMR, UV-pH titrations, and a customized evaluation method. The omni-interactive imidazole, amino, carboxylate, and thiolate moieties of ovothiol A are quantified in terms of 32 microscopic protonation constants, the relative concentrations of 16 microspecies, 6 pairwise interactivity parameters, and 8 protonation shifts. The highest and lowest imidazole basicities differ by a record-breaking five orders of magnitude, and the predominant thiolate protonation constant is by far the smallest known thiolate logK value. The latter provides an indication as to why ovothiol A occurs naturally under deep-water circumstances only. Since thiolate basicities are in correlation with thiol-disulfide redox potentials, the eight different, fine-tunable thiolate basicities offer versatile and highly specific antioxidant capacities within one single molecular skeleton. This work is the first complete microspeciation of a tetrabasic, nonsymmetrical natural compound.


Assuntos
Antioxidantes/química , Metilistidinas/química , Concentração de Íons de Hidrogênio , Estrutura Molecular
20.
Acta Pharm Hung ; 84(1): 21-37, 2014.
Artigo em Húngaro | MEDLINE | ID: mdl-24809164

RESUMO

This paper surveys the species-specific physico-chemical parameters (basicity and lipophilicity) and related biological functions of thyroid hormones (thyroxine, liothyronine and reverse liothyronine) and their biological precursors (tyrosine, monoiodotyrosine and diiodotyrosine). The protonation macroconstants were determined by 1H NMR-pH titrations while the microconstants were determined by a multimodal spectroscopic-deductive methodology using auxiliary derivatives of reduced complexity. Our results show that the different number and/or position of iodine are the key factors to influence the phenolate basicity. The ionization state of the phenolate site is crucial in the biosynthesis and protein binding of thyroid hormones. The role of the protonation state in the receptor binding was investigated by an in silico docking method. Microspecies of thyroid hormones were docked to the thyroid hormone receptor isoforms. Our results quantitate at the molecular level how the ionization stage and the charge distribution influence the protein binding. The anionic form of the carboxyl group is essential for the protein binding, whereas the protonated form of the amino group loosens it. The protonation state of the phenolate plays a role of secondary importance in the receptor binding. The combined results of docking and microspeciation studies show that microspecies of the highest concentration at the pH of blood are not the strongest binding ones. The site-specific lipophilicity of our investigated molecules was determined with the measurement of distribution coefficients at different pH using carboxymethyl- and O-methyl-derivatives to mimic the partition of some of the individual microspecies. Correction factors were determined and introduced. Our data show that the iodinated aromatic ring system is the definitive structural element that fundamentally determines the lipophilicity of thyroid hormones, whereas the protonation state of the aliphatic part is essential in receptor binding. The membrane transport of thyroid hormones can be well interpreted in terms of the site-specific lipophilicity. At physiological pH these biomolecules are strongly amphipathic due to the lipophilic aromatic rings and hydrophilic amino acid side chains which can well be the reason why thyroid hormones cannot cross membranes by passive diffusion and they even become constituents of biological membranes. The site-specific physico-chemical characterization of the thyroid hormones is of fundamental importance to understand their (patho) physiological behavior and also, to influence the therapeutic properties of their drug candidate derivatives at the molecular level.


Assuntos
Receptores dos Hormônios Tireóideos/metabolismo , Hormônios Tireóideos/química , Hormônios Tireóideos/metabolismo , Transporte Biológico , Simulação por Computador , Di-Iodotirosina/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Imageamento por Ressonância Magnética , Monoiodotirosina/metabolismo , Prótons , Especificidade da Espécie , Hormônios Tireóideos/biossíntese , Tiroxina/metabolismo , Tri-Iodotironina/metabolismo , Tri-Iodotironina Reversa/metabolismo
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