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1.
J Chromatogr A ; 1616: 460772, 2020 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-31839358

RESUMO

Amino acids are most often analyzed in reversed-phase liquid chromatography after a derivatization procedure to render them sufficiently hydrophobic and detectable with UV or fluorimetric detection. Simpler methods should be possible to avoid additional chemical reactions. We present an improved method to analyze free amino acids with unified chromatography, that is to say with a wide elution gradient starting with supercritical fluid chromatography (SFC) conditions (high percentage of carbon dioxide) and ending with high-performance liquid chromatography (HPLC) conditions (100% co-solvent). The mobile phase composition was carefully adjusted to permit the elution of 21 natural amino acids (among which 19 proteinogenic) with very good peak shapes from a zwitterionic cinchona-based stationary phase (Chiralpak ZWIX(+)). Chiral separation was not desired. The mobile phase finally selected comprised carbon dioxide and a co-solvent (methanol containing 2% water and 20 mM methanesulfonic acid), ranging from 10 to 100% in 7 min followed by 3 min re-equilibration at 25 °C. A reversed pressure gradient (15 to 11 MPa) and a reversed flow rate gradient (3 to 1 mL/min) were applied to avoid reaching the upper pressure limit of the pumping system (40 MPa) and to favor high chromatographic efficiency at every stage of the elution gradient. Detection was achieved with electrospray ionization-mass spectrometry (ESI(+)-MS). The method is then fast and straightforward as no derivatization step is necessary, and all isobaric species were chromatographically resolved. To demonstrate the applicability of the method, it was applied to the quantitation of amino acids in food supplements commonly consumed by sportsmen, containing taurine (a common natural amino acid) or branched-chain amino acids (BCAA), namely valine, and the isobaric leucine and isoleucine. A standard addition method was examined for sensitivity, linearity, repeatability and intermediate precision.


Assuntos
Aminoácidos/análise , Cromatografia Líquida de Alta Pressão , Cromatografia com Fluido Supercrítico , Análise de Alimentos/métodos , Espectrometria de Massas , Aminoácidos/química , Dióxido de Carbono/química , Cinchona/química , Suplementos Nutricionais/análise , Análise de Alimentos/instrumentação , Metanol/química , Reprodutibilidade dos Testes , Solventes/química , Espectrometria de Massas por Ionização por Electrospray
2.
J Chromatogr A ; 1611: 460574, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-31591039

RESUMO

Sixteen pairs of enantiomeric dipeptides were separated on four chiral ion-exchanger-type stationary phases based on Cinchona alkaloids. Anion-exchangers (QN-AX, QD-AX) and zwitterionic phases [ZWIX(+)™ and ZWIX(-)™] were studied in a comparative manner. The effects of the nature and concentrations of the mobile phase solvent components and organic salt additives on analyte retention and enantioseparation were systematically studied in order to get a deeper insight into the enantiorecognition mechanism. Moreover, experiments were performed in the temperature range 10-50 °C to calculate thermodynamic parameters like changes in standard enthalpy, Δ(ΔH°), entropy, Δ(ΔS°), and free energy, Δ(ΔG°) on the basis of van't Hoff plots derived from the ln α vs. 1/T curves. Elution sequences of the dipeptides were determined in all cases and, with a few exceptions, they were found to be opposite on the pseudoenantiomeric stationary phases as of QN-AX/QD-AX and of ZWIX(+) and ZWIX(-). The stereoselective retention mechanism is based on electrostatically driven intermolecular interactions supported by additional interaction increments mainly determined by the absolute configuration of the chiral C8 and C9 atoms of the quinine and quinidine moieties.


Assuntos
Alcaloides de Cinchona/química , Cinchona/química , Dipeptídeos/química , Extratos Vegetais/química , Cromatografia Líquida de Alta Pressão/instrumentação , Cromatografia Líquida de Alta Pressão/métodos , Estereoisomerismo , Temperatura , Termodinâmica
3.
J Chromatogr A ; 1612: 460689, 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-31733894

RESUMO

Chiralpak ZWIX(+) and ZWIX(-), are brush-type bonded-silica chiral stationary phases (CSPs), based on complex diastereomeric Cinchona alkaloids derivatives bearing both a positive and a negative charge. In the present study, we aimed to improve the understanding of retention and enantioseparation mechanisms of these CSPs employed in supercritical fluid chromatography (SFC). For this purpose, 9 other stationary phases were used as comparison systems: two of them are commercially available and bear only a positive charge (Chiralpak QN-AX and QD-AX) and the 7 others were designed purposely to be structurally similar to the parent ZWIX phases, but miss some portion of the complex ligand. First, cluster analysis was employed to identify similar and dissimilar behavior among the 11 stationary phases, where ionic interactions appeared to dominate the observed differences. Secondly, the stationary phases were characterized with linear solvation energy relationships (LSER) based on the SFC analysis of 161 achiral analytes and a modified version of the solvation parameter model to include ionic interactions. This served to compare the interaction capabilities for the 11 stationary phases and showed in particular the contribution of attractive and repulsive ionic interactions. Then the ZWIX phases were characterized for their enantioseparation capabilities with a set of 58 racemic probes. Discriminant analysis was applied to explore the molecular structural features that are useful to successful enantioseparation on the ZWIX phases. In particular, it appeared that the presence of positive charges in the analyte is causing increased retention but is not necessarily a favorable feature to enantiorecognition. On the opposite, the presence of negative charges in the analyte favors early elution and enantiorecognition. Finally, a smaller set of 30 pairs of enantiomers, selected by their structural diversity and different enantioseparation values on the ZWIX phases, were analyzed on all chiral phases to observe the contribution of each structural fragment of the chiral ligand on enantioselectivity. Molecular modelling of the ligands also helped in understanding the three-dimensional arrangement of each ligand, notably the intra-molecular hydrogen bonding or the possible contribution of ionic interactions. In the end, each structural element in the ZWIX phases appeared to be a significant contributor to successful enantioresolution, whether they contribute as direct interaction groups (ion-exchange functions) or as steric constraints to orientate the interacting groups towards the analytes.


Assuntos
Cromatografia com Fluido Supercrítico/métodos , Cinchona/química , Análise por Conglomerados , Análise Discriminante , Ligação de Hidrogênio , Íons/química , Oxazepam/química , Estereoisomerismo , Varfarina/química
4.
Molecules ; 24(22)2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31718009

RESUMO

By means of copper(I)-and ruthenium(II)-catalyzed click reactions of quinine- and quinidine-derived alkynes with azide-substituted chalcones a systematic series of novel cinchona-chalcone hybrid compounds, containing 1,4-disubstituted- and 1,5-disubstituted 1,2,3-triazole linkers, were synthesized and evaluated for their cytotoxic activity on four human malignant cell lines (PANC-1, COLO-205, A2058 and EBC-1). In most cases, the cyclization reactions were accompanied by the transition-metal-catalyzed epimerization of the C9-stereogenic centre in the cinchona fragment. The results of the in vitro assays disclosed that all the prepared hybrids exhibit marked cytotoxicity in concentrations of low micromolar range, while the C9-epimerized model comprising quinidine- and (E)-1-(4-(3-oxo-3-(3,4,5-trimethoxyphenyl)prop-1-en-1-yl)phenyl) fragments, connected by 1,5-disubstituted 1,2,3-triazole linker, and can be regarded as the most potent lead of which activity is probably associated with a limited conformational space allowing for the adoption of a relatively rigid well-defined conformation identified by DFT modelling. The mechanism of action of this hybrid along with that of a model with markedly decreased activity were approached by comparative cell-cycle analyses in PANC-1 cells. These studies disclosed that the hybrid of enhanced antiproliferative activity exerts significantly more extensive inhibitory effects in subG1, S and G2/M phases than does the less cytotoxic counterpart.


Assuntos
Chalcona/química , Chalcona/farmacologia , Técnicas de Química Sintética , Cinchona/química , Triazóis/química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Chalcona/síntese química , Humanos , Concentração Inibidora 50 , Modelos Moleculares , Conformação Molecular , Estrutura Molecular , Relação Estrutura-Atividade
5.
Bratisl Lek Listy ; 120(8): 576-580, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31379180

RESUMO

AIM: Quinine, a frequently used anti-malaria alkaloid isolated from the Cinchona bark, possesses numerous toxic properties, the majority of which arrive from a dysfunction of the gastrointestinal tract. Similarly, cinchonine, another alkaloid from the Cinchona bark, displays a great potential for treating malaria (especially the resistant forms). METHODS: In this work, we aimed to evaluate the effects of cinchonine on spontaneous and induced Wistar rat ileum contractions in order to uncover potential side effects that might arise after its application. RESULTS: Cinchonine produced a concentration-dependent spasmolytic activity, which was found to be reversible (i.e. disappeared after tissue wash-up), with an IC50 value of 273 µM. Furthermore, the mechanism of action of cinchonine at IC50 elucidated through experiments with acetylcholine and Ca2+-induced ileum contractions. The applied IC50 concentration of cinchonine statistically significantly prevented the occurrence of contractions after the application of specific agonist. The obtained results are in a range with the effects seen with standard receptor antagonists, i.e. atropine and verapamil. CONCLUSIONS: The obtained results showed that cinchonine inhibited both types of induced contractions, suggesting a Ca2+-channels mediated modus operandi (Fig. 4, Ref. 19).


Assuntos
Alcaloides/farmacologia , Alcaloides de Cinchona/farmacologia , Cinchona/química , Íleo/efeitos dos fármacos , Contração Muscular/efeitos dos fármacos , Parassimpatolíticos/farmacologia , Animais , Ratos , Ratos Wistar
6.
Faraday Discuss ; 218(0): 441-458, 2019 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-31120045

RESUMO

We present a development of the "Plasmodesma" dereplication method [Margueritte et al., Magn. Reson. Chem., 2018, 56, 469]. This method is based on the automatic acquisition of a standard set of NMR experiments from a medium sized set of samples differing by their bioactivity. From this raw data, an analysis pipeline is run and the data is analysed by leveraging machine learning approaches in order to extract the spectral fingerprints of the active compounds. The optimal conditions for the analysis are determined and tested on two different systems, a synthetic sample where a single active molecule is to be isolated and characterized, and a complex bioactive matrix with synergetic interactions between the components. The method allows the identification of the active compounds and performs a pharmacophoric deconvolution. The program is freely available on the Internet, with an interactive visualisation of the statistical analysis, at https://plasmodesma.igbmc.science.


Assuntos
Automação , Cinchona/química , Casca de Planta/química , Extratos Vegetais/análise , Internet , Aprendizado de Máquina
7.
J Chromatogr A ; 1596: 69-78, 2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-30837161

RESUMO

Amino acids play an important role in cellular processes and are building blocks for peptides and proteins, which take part in regulatory processes within each organism. Hence a large variety of biotechnologically or synthetically produced therapeutic drugs are peptides and proteins. Due to the chiral nature of amino acids and the large variety of common, uncommon and newly synthesized amino acid type compounds, stereoselective separation tools combined with mass spectrometric detection are important in research as well as purity control of therapeutics in industry. Since structural isomers and epimers of common amino acids are isobaric to each other, stereoselective separation is key to their identification. For this purpose zwitterionic quinine and quinidine type chiral stationary phases Chiralpak ZWIX(+) and Chiralpak ZWIX(-) were investigated for their separation performance for underivatized and 6-aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC; AccQ) derivatized proteinogenic amino acids, uncommon amino acids and their isobaric analogs such as allo-threonine, homoserine, allo-isoleucine and homocysteine by HPLC-ESI-QTOF-MS. Cystine and homocystine were reduced with dithiothreitol and S-alkylated with iodoacetic acid and iodoacetamide. In general, derivatization with AQC and thiol alkylation increased the detection sensitivity and resolution of acidic, basic and polar amino acids significantly (e.g. separation factor of Asp increased from 1.00 to 2.29 for Asp-AQC). In addition, throughout this study a u-13C15N-L-amino acid metabolomics mixture was added to the DL-amino acid test solution and used as a co-eluting peak assignment standard to identify the corresponding u-12C14N-L-amino acid peak and hence determine the elution order of the enantiomer pairs for complex mixtures within a single run, employing the same separation conditions for underivatized and AQC-derivatized amino acids and their isobaric analogs.


Assuntos
Aminoácidos/isolamento & purificação , Aminoquinolinas/química , Carbamatos/química , Técnicas de Química Analítica/métodos , Cromatografia Líquida de Alta Pressão , Quinidina/química , Quinina/química , Espectrometria de Massas em Tandem , Aminoácidos/química , Aminoquinolinas/isolamento & purificação , Carbamatos/isolamento & purificação , Técnicas de Química Analítica/instrumentação , Cinchona/química , Estereoisomerismo
8.
J Nat Med ; 73(2): 431-438, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30552602

RESUMO

New eight endophytic filamentous fungi were isolated from the young stems of Cinchona ledgeriana (Rubiaceae) cultivated in Japan. They were classified into four genera based on phylogenetic analysis of the nucleotide sequences of the internal transcribed spacers (ITS1 and ITS2), including the 5.8S ribosomal DNA region. Of the eight fungi isolated, there were five genera Cladosporium, one Meira sp., one Diaporthe sp. and one Penicillium sp. Genus of Cladosporium and Meira were first isolated fungi from Cinchona plant. In a previous study, we applied the same process to the same plant cultivated in Indonesia. The endophyte compositions for the two cultivation regions were found to differ at the genera level. The ability of Cinchona endophytes cultivated in Japan to produce Cinchona alkaloids was also assessed. We found that three isolates have producing ability of Cinchona alkaloids. However, the amount produced was very small compared to that produced by the endophytes of Indonesian Cinchona ledgeriana. In addition, the total content amount of Cinchona alkaloids, especially quinine, produced by the extract of Cinchona cultivated in Japan was much smaller than that from Indonesia. These finding indicate that endophyte composition has an influence on the Cinchona alkaloid content amount in the Cinchona ledgeriana host.


Assuntos
Alcaloides de Cinchona/metabolismo , Cinchona/microbiologia , Endófitos/isolamento & purificação , Fungos/isolamento & purificação , Alcaloides de Cinchona/isolamento & purificação , Endófitos/classificação , Endófitos/genética , Endófitos/metabolismo , Fungos/classificação , Fungos/genética , Fungos/metabolismo , Indonésia , Japão , Filogenia , Quinina/isolamento & purificação , Quinina/metabolismo , Rubiaceae
9.
Toxins (Basel) ; 10(12)2018 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-30477182

RESUMO

This article describes the discovery and use of the South American cinchona bark and its main therapeutic (and toxic) alkaloids, quinine and quinidine. Since the introduction of cinchona to Europe in the 17th century, it played a role in treating emperors and peasants and was central to colonialism and wars. Over those 400 years, the medical use of cinchona alkaloids has evolved from bark extracts to chemical synthesis and controlled clinical trials. At the present time, the use of quinine and quinidine has declined, to a large extent due to their toxicity. However, quinine is still being prescribed in resource-limited settings, in severe malaria, and in pregnant women, and quinidine made a limited comeback in the treatment of several cardiac and neurological syndromes. In addition, the article presents more recent studies which improved our understanding of cinchona alkaloids' pharmacology. The knowledge gained through these studies will hopefully lead to a wider use of these drugs in precision medicine and to design of new generation, safer quinine and quinidine derivatives.


Assuntos
Alcaloides de Cinchona/uso terapêutico , Cinchona , Malária/tratamento farmacológico , Doenças do Sistema Nervoso/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Antiarrítmicos/uso terapêutico , Antimaláricos/uso terapêutico , Humanos , Casca de Planta/química
10.
PLoS One ; 13(10): e0205193, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30289893

RESUMO

This paper describes the synthesis and anticholinesterase potency of Cinchona-based alkaloids; ten quaternary derivatives of cinchonines and their corresponding pseudo-enantiomeric cinchonidines. The quaternization of quinuclidine moiety of each compound was carried out with groups diverse in their size: methyl, benzyl and differently meta- and para-substituted benzyl groups. All of the prepared compounds reversibly inhibited human butyrylcholinesterase and acetylcholinesterase with Ki constants within nanomolar to micromolar range. Five cinchonidine derivatives displayed 95-510 times higher inhibition selectivity to butyrylcholinesterase over acetylcholinesterase and four were potent butyrylcholinesterase inhibitors with Ki constants up to 100 nM, of which N-para-bromobenzyl cinchonidinium bromide can be considered a lead for further modifications and optimizations for possible use in the treatment of neurodegenerative diseases.


Assuntos
Butirilcolinesterase/química , Inibidores da Colinesterase/farmacologia , Alcaloides de Cinchona/química , Desenho de Fármacos , Doenças Neurodegenerativas/tratamento farmacológico , Acetilcolinesterase/química , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/uso terapêutico , Cinchona/química , Ensaios Enzimáticos , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Estereoisomerismo , Relação Estrutura-Atividade
11.
Org Biomol Chem ; 16(35): 6470-6478, 2018 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-30151544

RESUMO

The bifunctional nature of the cinchonidine squaramides has been successfully employed to catalyze the enantioselective 1,4-Michael addition reaction of pyrazolin-5-ones with 2-enoylpyridines under mild reaction conditions. Through this methodology, a broad range of optically active heterocyclic derivatives bearing both pyrazole and pyridine motifs have been synthesized in yields up to 88% and enantiomeric excess up to 96%.


Assuntos
Cinchona/química , Pirazolonas/química , Piridinas/química , Quinina/análogos & derivados , Catálise , Quinina/química , Estereoisomerismo , Especificidade por Substrato
12.
Med Hypotheses ; 117: 16-20, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30077188

RESUMO

Francisco José de Goya y Lucientes is one of the major figures of European art. From royal portraits to bizarre, grotesque illustrations, his legacy demonstrates a tortured genius, generating some of the most compelling art ever produced. His story is also the story of Spain during one of the most tumultuous passages of its history. In the winter of 1792-93, Goya experienced a mysterious illness resulting in lifelong deafness. After that, his work became more negative, with thick, bold strokes of dark colour. Scholars have suggested various diagnoses on the basis of Master's symptoms, but the exact nature of the illness has never been identified.


Assuntos
Arte , Surdez/história , Pinturas , Acidente Vascular Cerebral/história , Cinchona/efeitos adversos , Síndrome de Cogan/história , Pessoas Famosas , História do Século XIX , Humanos , Intoxicação por Chumbo/história , Malária/história , Transtornos Psicóticos/história , Espanha , Sífilis/história , Síndrome Uveomeningoencefálica/história
13.
J Chromatogr A ; 1558: 29-36, 2018 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-29759645

RESUMO

A cardinal requirement for effective 2D-HPLC separations is sufficient complementarity in the retention profiles of first and second dimension separations. It is shown that retention and enantioselectivity of chiral selectors derived from cinchona alkaloids can be conveniently modulated by structural variation of the carbamate residue of the quinine/quinidine carbamate ligand of such chiral stationary phases (CSP). A variety of aliphatic and aromatic residues have been tested in comparison to non-carbamoylated quinine CSP. Various measures of orthogonality have been utilized to derive the CSP that is most complementary to the tert-butylcarbamoylated quinine CSP (tBuCQN CSP), which is commercially available as Chiralpak QN-AX column. It turned out that O-9-(2,6-diisopropylphenylcarbamoyl)-modified quinine is most promising in this respect. Its implementation as a complementary CSP for the separation of amino acids derivatized with Sanger's reagent (2,4-dinitrophenylated amino acids) in the first dimension combined with a tBuCQN CSP in the second dimension revealed successful enantiomer separations in a comprehensive chiral×chiral 2D-HPLC setup. However, the degree of complementarity could be greatly enhanced when simultaneously the absolute configurations were exchanged from quinine to quinidine in the chiral selector of the first dimension separation resulting in opposite elution orders of the enantiomers in the two dimensions. The advantage of such a chiral×chiral over achiral×chiral 2D-HPLC setup, amongst others, is the perfect compatibility of the mobile phase because in both dimensions the identical eluent can be used.


Assuntos
Aminoácidos/análise , Carbamatos/química , Cromatografia Líquida de Alta Pressão/métodos , Cinchona/química , Aminoácidos/química , Análise de Componente Principal , Quinidina/química , Quinolinas/química , Estereoisomerismo
14.
J Chromatogr A ; 1554: 117-122, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29699870

RESUMO

Chinoline alkaloids found in Cinchona bark still play an important role in medicine, for example as antimalarial and antiarrhythmic drugs. For the first time Supercritical Fluid Chromatography has been utilized for their separation. Six respective derivatives (dihydroquinidine, dihydroquinine, quinidine, quinine, cinchonine and cinchonidine) could be resolved in less than 7 min, and three of them quantified in crude plant extracts. The optimum stationary phase showed to be an Acquity UPC2 Torus DEA 1.7 µm column, the mobile phase comprised of CO2, acetonitrile, methanol and diethylamine. Method validation confirmed that the procedure is selective, accurate (recovery rates from 97.2% to 103.7%), precise (intra-day ≤2.2%, inter-day ≤3.0%) and linear (R2 ≥ 0.999); at 275 nm the observed detection limits were always below 2.5 µg/ml. In all of the samples analyzed cinchonine dominated (1.87%-2.30%), followed by quinine and cinchonidine. Their total content ranged from 4.75% to 5.20%. These values are in good agreement with published data, so that due to unmatched speed and environmental friendly character SFC is definitely an excellent alternative for the analysis of these important natural products.


Assuntos
Alcaloides/análise , Cinchona/química , Alcaloides/química , Cromatografia com Fluido Supercrítico , Cinchona/metabolismo , Alcaloides de Cinchona/análise , Limite de Detecção , Casca de Planta/química , Casca de Planta/metabolismo , Extratos Vegetais/química , Quinidina/análogos & derivados , Quinidina/análise , Quinina/análise
15.
J Sep Sci ; 41(6): 1355-1364, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29364568

RESUMO

In the enantiomeric separation of highly polar compounds, a traditionally challenging task for high-performance liquid chromatography, ion-exchange chiral stationary phases have found the main field of application. In this contribution, we present a series of novel anion-exchange-type chiral stationary phases for enantiomer separation of protected amino phosphonates and N-protected amino acids. Two of the prepared selectors possessed a double and triple bond within a single molecule. Thus, they were immobilized onto silica support employing either a thiol-ene (radical) or an azide-yne (copper(I)-catalyzed) click reaction. We evaluated the selectivity and the effect of immobilization proceeding either by the double bond of the Cinchona alkaloid or a triple bond of the carbamoyl moiety on the chromatographic performance of the chiral stationary phases using analytes with protecting groups of different size, flexibility, and π-acidity. The previously observed preference toward protecting groups possessing π-acidic units, which is a typical feature of Cinchona-based chiral stationary phases, was preserved. In addition, increasing the bulkiness of the selectors' carbamoyl units leads to significantly reduced retention times, while very high selectivity toward the tested analytes is retained.


Assuntos
Cinchona/química , Cromatografia Líquida de Alta Pressão , Cromatografia por Troca Iônica , Estrutura Molecular , Estereoisomerismo
16.
J Chromatogr A ; 1534: 55-63, 2018 Jan 26.
Artigo em Inglês | MEDLINE | ID: mdl-29279137

RESUMO

Quality-by-Design approach for enantioselective HPLC method development surpasses Quality-by-Testing in offering the optimal separation conditions with the least number of experiments and in its ability to describe the method's Design Space visually which helps to determine enantiorecognition to a significant extent. Although some schemes exist for enantiomeric separations on Cinchona-based zwitterionic stationary phases, the exact design space and the weights by which each of the chromatographic parameters influences the separation have not yet been statistically studied. In the current work, a screening design followed by a Response Surface Methodology optimization design were adopted for enantioseparation optimization of 3 model drugs namely the acidic Fmoc leucine, the amphoteric tryptophan and the basic salbutamol. The screening design proved that the acid/base additives are of utmost importance for the 3 chiral drugs, and that among 3 different pairs of acids and bases, acetic acid and diethylamine is the couple able to provide acceptable resolution at variable conditions. Visualization of the response surface of the retention factor, separation factor and resolution helped describe accurately the magnitude by which each chromatographic factor (% MeOH, concentration and ratio of acid base modifiers) affects the separation while interacting with other parameters. The global optima compromising highest enantioresolution with the least run time for the 3 chiral model drugs varied extremely, where it was best to set low % methanol with equal ratio of acid-base modifiers for the acidic drug, very high % methanol and 10-fold higher concentration of the acid for the amphoteric drug while 20 folds of the base modifier with moderate %methanol were needed for the basic drug. Considering the selected drugs as models for many series of structurally related compounds, the design space defined and the optimum conditions computed are the key for method development on cinchona-based chiral stationary phases.


Assuntos
Química Farmacêutica/métodos , Cromatografia Líquida de Alta Pressão , Cinchona/química , Preparações Farmacêuticas/isolamento & purificação , Ácidos/química , Ácidos/isolamento & purificação , Aminoácidos/química , Metanol/química , Estereoisomerismo
17.
Org Biomol Chem ; 15(37): 7753-7757, 2017 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-28891567

RESUMO

An operationally simple protocol for the enantioselective electrophilic α-cyanation of ß-keto amides catalyzed by cinchona-derived catalysts has been demonstrated. The resulting products could be obtained with good to high enantioselectivities (up to 88% ee) and with excellent yields (up to 94%) by employing the mild active 4-acetylphenyl cyanate as the cationic cyano source in the catalytic asymmetric α-cyanation reaction.


Assuntos
Alcaloides/química , Amidas/química , Cinchona/química , Cianetos/síntese química , Catálise , Cianetos/química , Estrutura Molecular , Estereoisomerismo
18.
Metallomics ; 9(8): 1132-1141, 2017 08 16.
Artigo em Inglês | MEDLINE | ID: mdl-28737782

RESUMO

Recently, we demonstrated that ferrocene-containing compounds with a cinchona moiety displayed marked anticancer activity. Here we report on the effects of the most promising isomers encompassing quinine- (compounds 4 and 5) and quinidine-epimers (compounds 6 and 7) - synthesized using improved methods providing controlled diastereoselectivity - in three different human multidrug resistant (MDR) cancer cell lines and their sensitive counterparts (non-small cell lung carcinoma NCI-H460/R/NCI-H460, colorectal carcinoma DLD1-TxR/DLD1 and glioblastoma U87-TxR/U87). We observed that the presence of the MDR phenotype did not diminish the activity of the compounds suggesting that ferrocene quinine- and quinidine-epimers are not substrates for P-glycoprotein, which has been indicated as a major mechanism of MDR in the cell lines used. Considering that metal-based anticancer agents mainly act by increasing ROS production, we investigated the potential of ferrocene-quinidine epimers to generate ROS. We found that 6 and 7 more readily increased ROS production and induced mitochondrial damage in MDR cancer cells. According to cell death analysis, 6 and 7 were more active against MDR cancer cells showing collateral sensitivity. In addition, our data suggest that these compounds could act as inhibitors of autophagy. Importantly, simultaneous treatments of 6 and 7 with paclitaxel (PTX) increased the sensitivity of MDR cancer cells to PTX. In conclusion, the ferrocene-quinidine epimers, besides being selective towards MDR cancer cells, could also possess potential to overcome PTX resistance.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Chalconas/química , Cinchona/química , Compostos Ferrosos/química , Neoplasias Pulmonares/patologia , Metalocenos/química , Paclitaxel/farmacologia , Triazóis/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Chalconas/metabolismo , Cinchona/metabolismo , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Compostos Ferrosos/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Metalocenos/metabolismo , Oxidantes/química , Oxidantes/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Triazóis/metabolismo , Células Tumorais Cultivadas
19.
J Complement Integr Med ; 14(4)2017 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-28665790

RESUMO

Background Quinine (QT) is an important anti-malarial drug; however, there is little information about its effects on the gut. Therefore, this study aimed to investigate the effects of a therapeutic dose of QT on the healing of gastric ulcer in rats. Methods Male Wistar rats weighing 150-200 g were divided into three groups: control rats without ulcer (group 1), ulcerated rats treated with 1 mL/kg (p.o.) normal saline (NS) (group 2), and ulcerated rats treated with 10 mg/kg (p.o.) QT (group 3). Ulcers were induced by serosal application of 80 % acetic acid to the stomach of rats anaesthetized with 50 mg/kg thiopentone sodium and treatment was given three times daily. Healing was assessed on days 3, 7 and 10 after ulcer induction by macroscopic measurement of: ulcer area, histology, lipid peroxidation, superoxide dismutase activity and gastric mucus secretion. Results At day 3, there was no significant difference (p>0.05) in ulcer areas between NS- and QT-treated rats. By day 10, however, the percentage area healed in NS treated (59.6±2.35 %) was significantly higher (p<0.05) than in QT rats (49.0±2.20 %) and clearing of inflammatory cells and re-epithelization was greater in NS-treated group. By days 7 and 10, lipid peroxidation was significantly higher in QT animals, when compared with NS-treated rats and controls (p<0.05). Superoxide dismutase activity and mucus secretion were significantly (p<0.05) higher in NS-treated than QT-treated rats. Conclusions QT delayed ulcer healing by prolonging the inflammatory phase of healing, increasing oxidative stress, reducing antioxidant activity and gastric mucus secretion.


Assuntos
Cinchona/efeitos adversos , Mucosa Gástrica/efeitos dos fármacos , Extratos Vegetais/efeitos adversos , Quinina/efeitos adversos , Úlcera Gástrica , Cicatrização/efeitos dos fármacos , Ácido Acético , Animais , Cinchona/química , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patologia , Inflamação/etiologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Muco/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Quinina/uso terapêutico , Ratos Wistar , Reepitelização/efeitos dos fármacos , Estômago , Úlcera Gástrica/induzido quimicamente , Úlcera Gástrica/metabolismo , Úlcera Gástrica/patologia , Superóxido Dismutase/metabolismo , Úlcera/induzido quimicamente , Úlcera/metabolismo , Úlcera/patologia
20.
Org Biomol Chem ; 15(24): 5227-5235, 2017 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-28598472

RESUMO

Herein we report a two-step sequence for the preparation of amides starting from azides and enolisable aldehydes. The reaction proceeded via the formation of triazoline intermediates that were converted into amides via Lewis acid catalysis. Preliminary studies on the preparation of triazolines under chiral phase transfer catalysis are also presented, demonstrating that enantioenriched amides could be prepared from achiral aldehydes in moderate to low enantioselectivity.


Assuntos
Aldeídos/química , Amidas/síntese química , Azidas/química , Cinchona/química , Compostos de Amônio Quaternário/química , Amidas/química , Catálise , Estrutura Molecular , Sais/química
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