Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 2.021
Filtrar
1.
Int J Mol Sci ; 22(5)2021 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-33652675

RESUMO

A priority of modern agriculture is to use novel and environmentally friendly plant-growth promoter compounds to increase crop yields and avoid the indiscriminate use of synthetic fertilizers. Brassinosteroids are directly involved in the growth and development of plants and are considered attractive candidates to solve this problem. Obtaining these metabolites from their natural sources is expensive and cumbersome since they occur in extremely low concentrations in plants. For this reason, much effort has been dedicated in the last decades to synthesize brassinosteroids analogs. In this manuscript, we present the synthesis and characterization of seven steroidal carbamates starting from stigmasterol, ß-sitosterol, diosgenin and several oxygenated derivatives of it. The synthesis route for functionalization of diosgenin included epoxidation and epoxy opening reactions, reduction of carbonyl groups, selective oxidation of hydroxyl groups, among others. All the obtained compounds were characterized by 1H and 13C NMR, HRMS, and their melting points are also reported. Rice lamina inclination test performed at different concentrations established that all reported steroidal carbamates show plant-growth-promoting activity. A molecular docking study evaluated the affinity of the synthesized compounds towards the BRI1-BAK1 receptor from Arabidopsis thaliana and three of the docked compounds displayed a binding energy lower than brassinolide.


Assuntos
Arabidopsis/crescimento & desenvolvimento , Carbamatos , Simulação de Acoplamento Molecular , Oryza/crescimento & desenvolvimento , Reguladores de Crescimento de Planta , Brassinosteroides/química , Carbamatos/síntese química , Carbamatos/química , Carbamatos/farmacologia , Reguladores de Crescimento de Planta/síntese química , Reguladores de Crescimento de Planta/química , Reguladores de Crescimento de Planta/farmacologia , Esteroides Heterocíclicos/química
2.
J Chromatogr A ; 1643: 462065, 2021 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-33780886

RESUMO

A short RNA with the sequence of the antisense strand of Patisiran has been selected as test material for the investigation of its common impurities using three different two-dimensional liquid chromatography (2D-LC) platforms. On the one hand, a quinine (QN) carbamate-based weak anion-exchange (AX) stationary phase (QN-AX) and a classical C18 reversed phase (RP) stationary phase in ion-pair (IP) mode with tripropylammonium acetate, respectively, have been used in the first dimension (1D) to provide the selectivity for impurities formed during the synthesis of the RNA. In the next step, certain peaks of interest from 1D have been transferred by multiple-heart-cutting (MHC) into a 2D in which an ESI-MS-compatible non-ionpairing RP method has been used for desalting via a diverter valve to remove non-volatile phosphate buffer components and ion-pair agents, respectively. Thus, a sensitive electrospray-ionization quadrupole time of flight mass spectrometry (ESI-TOF-MS) analysis of resolved impurity peaks of the siRNA has become possible under MS-friendly conditions. With both 2D-LC setups, peak purity of the ON has been evaluated by selective comprehensive (high resolution) sampling of the main peak. In a third MHC 2D-LC approach, the QN-AX LC mode was online coupled with the IP-RPLC in the 2D using UV detection. It allows the separation of additional impurities which coeluted in the first dimension. The potential of these methods for comprehensive impurity profiling of ON therapeutics is illustrated and discussed.


Assuntos
Cromatografia por Troca Iônica/métodos , Cromatografia de Fase Reversa/métodos , RNA Interferente Pequeno/análise , Espectrometria de Massas por Ionização por Electrospray/métodos , Sequência de Bases , Carbamatos/química , Cromatografia Líquida de Alta Pressão , Quinina/química , RNA Interferente Pequeno/química
3.
Food Chem ; 349: 129157, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33578248

RESUMO

Carbendazim (CBZ) pesticide residues in food products have become a growing concern in recent years. Herein, a sensitive biosensor for detecting CBZ was developed based on luminescent resonance energy transfer (LRET) from aptamer labeled upconversion nanoparticles (UCNPs, donor) to manganese dioxide (MnO2, acceptor) nanosheets. The strong overlap between the absorption spectrum of MnO2 and the UCNPs fluorescence emission allowed the luminescence quenching. With the addition of CBZ, it tended to bind with specific aptamers, which culminated in the UCNPs-aptamer dropping off MnO2 nanosheets and restoring the fluorescence. A linear calibration plot between logarithmic CBZ concentration and fluorescence intensity was acquired in the range of 0.1-5000 ng·mL-1, with a limit of detection 0.05 ng·mL-1, indicating that the UCNPs- MnO2 aptasensor is a rapid, sensitive and specific quantitative detection platform for CBZ. Furthermore, the precision and accuracy of the developed LRET biosensor was validated by HPLC method with no significant differences.


Assuntos
Benzimidazóis/análise , Técnicas Biossensoriais/métodos , Carbamatos/análise , Transferência Ressonante de Energia de Fluorescência/métodos , Análise de Alimentos/métodos , Contaminação de Alimentos/análise , Limite de Detecção , Aptâmeros de Nucleotídeos/química , Benzimidazóis/química , Carbamatos/química , Compostos de Manganês/química , Nanopartículas/química , Óxidos/química
4.
Carbohydr Polym ; 251: 117015, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33152849

RESUMO

We report a facile chemical method to convert the hydroxyl groups of hydroxypropyl cellulose (HPC) into carbamates. It was achieved by the reaction of HPC with N-methyl carbamoylimidazole, which is a safe and easy to handle replacement for the particularly hazardous reagent methyl isocyanate. Using a series of HPC with a range of molar substitution of hydroxypropyl groups, we synthesized HPC methylcarbamates showing lower critical solution temperature (LCST) in the range between 94 and 15 °C. A linear dependence of LCST versus methylcarbamate degree of substitution is observed. The lower the initial hydroxypropyl content of HPC, the greater the effect of methylcarbamate on the LCST. Surface tension study showed that methylcarbamate modification has an insignificant effect on the hydrophilic-hydrophobic balance of the macromolecules below LCST unless the molecular substitution of hydroxypropyl groups is so low (0.8) that the native cellulose OH groups can react with N-methyl carbamoylimidazole.


Assuntos
Celulose/análogos & derivados , Transição de Fase , Carbamatos/química , Celulose/química , Interações Hidrofóbicas e Hidrofílicas , Polímeros/química , Soluções , Temperatura
5.
Food Chem ; 345: 128839, 2021 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-33340894

RESUMO

A ratiometric fluorescent sensor was facilely fabricated using innate fluorescence of carbendazim (MBC) and fluorescent UiO-67 to sensitively and selectively detect MBC in food matrixes. The innate fluorescence of MBC provided a signal at 311 nm (F311), and the fluorescent UiO-67 at 408 nm (F408) could recognize MBC through π-π stacking inducing fluorescent quenching relied on photoelectron transfer (PET). The ratio (F311/F408) of the fluorescence enhancement of MBC and the quenching of UiO-67 linearly responded to the MBC concentrations of 0-47.6 µmol/L with a low limit of detection (LOD) of 3.0 × 10-3 µmol/L. The reverse response signals of the sensor enhanced the sensitivity toward MBC and presented remarkable anti-interference capability in complex matrices. The as-prepared sensor was applied to detect MBC residues in apple, cucumber and cabbage, obtaining satisfactory accuracy and precision with the recovery of 90.82-103.45% and RSDs of lower than 3.03%.


Assuntos
Benzimidazóis/análise , Benzimidazóis/química , Carbamatos/análise , Carbamatos/química , Análise de Alimentos/métodos , Frutas/química , Estruturas Metalorgânicas/química , Verduras/química , Contaminação de Alimentos/análise , Limite de Detecção , Resíduos de Praguicidas/análise , Resíduos de Praguicidas/química , Espectrometria de Fluorescência
6.
Food Chem ; 337: 127755, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-32777567

RESUMO

Since the beginning of the widespread use of pesticides, their removal from food has become a serious concern. In this study, the removal of residual pesticides (malathion and carbosulfan) from pak choi via treatment with ozonated water was investigated. Under the optimal treatment conditions, i.e., 2.0 mg/L ozonated water and a treatment duration of 15 min, malathion and carbosulfan were degraded by 53.0 and 33.0%, respectively, without any significant changes in color. Even though there was a slight decrease in vitamin C content (~7.9 mg/100 g) following the treatments, a significant decrease in the microbial colonies on the vegetables was observed. Additionally, the pesticide degradation mechanism showed good fitting with a "first + first"-order kinetic model (R2 > 0.9), and the slope (k) indicated that ozone had a more prominent degradation effect on malathion than on carbosulfan. Therefore, this study provides a theoretical basis for controlling agricultural pesticide residues in household applications.


Assuntos
Brassica rapa/química , Carbamatos/química , Carbamatos/isolamento & purificação , Malation/química , Malation/isolamento & purificação , Ozônio/química , Contaminação de Alimentos , Resíduos de Praguicidas/química , Resíduos de Praguicidas/isolamento & purificação , Verduras/química
7.
Food Chem ; 339: 128085, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33152876

RESUMO

Due to the excessive use of fungicides, pesticide residues have become a growing concern in recent years. Herein, we demonstrated an easy-prepared and low-cost surface enhanced Raman Scattering (SERS) chip composed of 3D silver microspheres (AgMSs) pattern for the quantitative testing of carbendazim in Chinese tea. Compared with the common monolayer SERS substrate, the 3D patterns formed by self-assembly AgMSs with fine nanostructure can offer much more aggregation-induced hotspots and generate strong 3D synergetic effects. Furthermore, when the thickness of the 3D pattern exceeded 6 µm, we replaced the conductive supporting coatings using the glass slides to reduce the cost without any impact on SERS properties. The prepared 3D chips achieved the determination of carbendazim within the linear range of 0.1-10 mg/L and the detection limit of 0.01 mg/L. It is simple and sensitive enough for the detection of most pesticide residues or other harmful organic molecules in our food or environment.


Assuntos
Benzimidazóis/análise , Carbamatos/análise , Contaminação de Alimentos/análise , Microesferas , Resíduos de Praguicidas/análise , Prata/química , Análise Espectral Raman , Chá/química , Benzimidazóis/química , Carbamatos/química , Cor , Humanos , Limite de Detecção , Resíduos de Praguicidas/química , Fatores de Tempo
8.
Chemosphere ; 255: 127013, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32679631

RESUMO

In order to obtain higher agricultural yields, the use of chemical substances has been increased to prevent the proliferation of pests, as well as ensuring durability in the storage of the food produced. Such substances are known as pesticides that may well present risks to human health and the environment. In the presence of metal ions, these substances can interact forming new species with different characteristics. Carbendazim (MBC) is an example of a harmful pesticide, which has atoms of nitrogen and oxygen in its structure that can form complexes with metal ions. Thus, in this work has studied the interaction between the copper (II) metal ion and carbendazim and its formation in natural water. The Cu-MBC complex showed a reduction peak of 0.007 V and an oxidation peak of 0.500 V, with characteristics of a quasi-reversible process under a glassy carbon electrode. By anodic stripping voltammetry, a different behavior was observed in the interaction of copper and carbendazim in ultrapure water and Billings dam water; however, it was possible to observe the complex in both samples. Carbendazim in the presence of the metal shows lower oxidation potential value, indicating the influence of the metal on the electrochemical response of the pesticide.


Assuntos
Benzimidazóis/química , Carbamatos/química , Cobre/química , Poluentes Químicos da Água/química , Carbono/química , Técnicas Eletroquímicas/métodos , Eletrodos , Oxirredução
9.
Mol Pharmacol ; 98(2): 156-167, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32591477

RESUMO

The natural product (+)-discodermolide (DDM) is a microtubule stabilizing agent and potent inducer of senescence. We refined the structure of DDM and evaluated the activity of novel congeners in triple negative breast and ovarian cancers, malignancies that typically succumb to taxane resistance. Previous structure-activity analyses identified the lactone and diene as moieties conferring anticancer activity, thus identifying priorities for the structural refinement studies described herein. Congeners possessing the monodiene with a simplified lactone had superior anticancer efficacy relative to taxol, particularly in resistant models. Specifically, one of these congeners, B2, demonstrated 1) improved pharmacologic properties, specifically increased maximum response achievable and area under the curve, and decreased EC50; 2) a uniform dose-response profile across genetically heterogeneous cancer cell lines relative to taxol or DDM; 3) reduced propensity for senescence induction relative to DDM; 4) superior long-term activity in cancer cells versus taxol or DDM; and 5) attenuation of metastatic characteristics in treated cancer cells. To contrast the binding of B2 versus DDM in tubulin, X-ray crystallography studies revealed a shift in the position of the lactone ring associated with removal of the C2-methyl and C3-hydroxyl. Thus, B2 may be more adaptable to changes in the taxane site relative to DDM that could account for its favorable properties. In conclusion, we have identified a DDM congener with broad range anticancer efficacy that also has decreased risk of inducing chemotherapy-mediated senescence. SIGNIFICANCE STATEMENT: Here, we describe the anticancer activity of novel congeners of the tubulin-polymerizing molecule (+)-discodermolide. A lead molecule is identified that exhibits an improved dose-response profile in taxane-sensitive and taxane-resistant cancer cell models, diminished risk of chemotherapy-mediated senescence, and suppression of tumor cell invasion endpoints. X-ray crystallography studies identify subtle changes in the pose of binding to ß-tubulin that could account for the improved anticancer activity. These findings support continued preclinical development of discodermolide, particularly in the chemorefractory setting.


Assuntos
Alcanos/química , Carbamatos/química , Lactonas/síntese química , Neoplasias Ovarianas/metabolismo , Pironas/química , Neoplasias de Mama Triplo Negativas/metabolismo , Moduladores de Tubulina/síntese química , Células A549 , Área Sob a Curva , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Feminino , Humanos , Lactonas/química , Lactonas/farmacologia , Estrutura Molecular , Neoplasias Ovarianas/tratamento farmacológico , Taxoides/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Moduladores de Tubulina/química , Moduladores de Tubulina/farmacologia
10.
J Chromatogr A ; 1623: 461174, 2020 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-32505278

RESUMO

A new class of chitosan derivatives with an isopropylthiourea at the 2-position and various carbamates at the 3,6-positions of the glucosamine skeleton was synthesized by the selective thiocarbamoylation of the 2-amino group. The chiral stationary phases (CSPs) were then prepared by coating the obtained chitosan 2-isopropylthiourea-3,6-dicarbamate derivatives onto silica gel. The enantioseparation property of the chitosan-based CSPs was assessed with twelve racemates by high-performance liquid chromatography (HPLC). The CSPs displayed a characteristic enantioseparation power, which seemed to be significantly affected by the 3,6-substituents of the glucosamine unit. The chitosan derivatives with the 3,6-diphenylcarbamate, except for 2-methylphenylcarbamate, possessed higher enantioseparation abilities than those with the 3,6-dicyclohexylcarbamate. Compared to other chitosan derivatives with 2-various substituents and commercialized Chiralcel OD, the chitosan 2-isopropylthiourea derivatives revealed a relatively higher enantioselectivity for some racemic compounds.


Assuntos
Quitosana/análogos & derivados , Cromatografia Líquida de Alta Pressão/métodos , Carbamatos/química , Celulose/análogos & derivados , Celulose/química , Glucosamina/química , Fenilcarbamatos/química , Sílica Gel/química , Estereoisomerismo , Tioureia/análogos & derivados
11.
Ecotoxicol Environ Saf ; 201: 110729, 2020 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-32485491

RESUMO

The transformation of carbosulfan (CSN) in apples was investigated during oven-drying, microwave drying, and sun-drying. CSN transformed primarily into carbofuran (COA) during these drying processes. The conversion kinetics of CSN and COA was fitted by curve regression and mainly conformed to quadratic models (R2 = 0.70-0.97). Oven-drying promoted the transformation of CSN into COA. Microwave drying resulted in the highest scavenging capacity against CSN and COA (41%-100%). Moreover, a transformation mechanism was proposed on the basis of density functional theory (DFT) calculation. The COA originated from a series of chemical reactions involving hydroxyl substitution, cleavage, and oxidation; this result was further confirmed on the basis of molecular electrostatic potential (MEP) and molecular orbital theory. Furthermore, the toxicity and stability of CSN and COA were evaluated with the T.E.S.T. program. COA was less toxic than CSN to aquatic organisms but more toxic than CSN to rats. Therefore, COA production should be avoided during drying. Microwave drying was found to be the optimum choice for drying apples.


Assuntos
Carbamatos/metabolismo , Dessecação/métodos , Manipulação de Alimentos/métodos , Malus/química , Animais , Organismos Aquáticos/efeitos dos fármacos , Carbamatos/química , Carbamatos/toxicidade , Carbofurano/química , Carbofurano/metabolismo , Carbofurano/toxicidade , Dessecação/instrumentação , Manipulação de Alimentos/instrumentação , Depuradores de Radicais Livres/análise , Ratos
12.
Int J Pharm Compd ; 24(3): 242-245, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32401744

RESUMO

Revefenacin inhalation solution, a long-acting muscarinic antagonist (LAMA), and formoterol fumarate inhalation solution, a long-acting ß-agonist (LABA), are indicated for the maintenance treatment of patients with chronic obstructive pulmonary disease. LAMA or LABA monotherapy, or a combination of LAMA/LABA for more severe symptoms, is recommended as first-line treatment in this patient population. We conducted a study to test the physicochemical properties of revefenacin and formoterol fumarate inhalation solution admixture in support of a clinical trial evaluating the safety of these nebulized bronchodilators, administered in sequence, and as a combination, in patients with chronic obstructive pulmonary disease (NCT03573817). The admixture of these two products was evaluated for changes in appearance, pH, osmolality, active drug content, purity, and impurity/degradant levels at 25°C for up to 25 hours. No substantial changes were observed in the physicochemical properties of revefenacin inhalation solution and formoterol fumarate inhalation solution admixture, demonstrating the physicochemical compatibility and stability of the two drugs in solution for up to 25 hours at room temperature.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2 , Benzamidas/farmacologia , Carbamatos/farmacologia , Fumarato de Formoterol/farmacologia , Doença Pulmonar Obstrutiva Crônica , Administração por Inalação , Agonistas de Receptores Adrenérgicos beta 2/química , Agonistas de Receptores Adrenérgicos beta 2/farmacologia , Benzamidas/química , Carbamatos/química , Quimioterapia Combinada , Humanos
13.
An Acad Bras Cienc ; 92(1): e20181021, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32401841

RESUMO

Fosamprenavir calcium is an amprenavir prodrug of the protease inhibitors class used in the treatment of patients with acquired immunodeficiency syndrome (AIDS). Different solid forms of this drug are described in patents, in this sense studies on the physico-chemical characterization and stability are relevant for the selection of a solid form with adequate features for pharmaceutical purposes. In the present work form I (commercial) and amorphous of fosamprenavir calcium were characterized by the techniques of Differential Scanning Calorimetry (DSC), Thermogravimetry (TGA), Powder X-ray Diffraction (PXRD), Fourier-Transform Infrared Spectroscopy (FTIR) and Scanning Electron Microscopy (SEM). Furthermore, the chemical and polymorphic stability of the commercial form were evaluated by DSC, PXRD, FTIR and High-Performance Liquid Chromatography (HPLC). In the studies of characterization, thermal analyses allied to spectroscopic methods (PXRD and FTIR) demonstrated that the presence of water in the crystalline structure of Form I is fundamental for maintaining its crystallinity. In studies of accelerated stability the techniques of DSC, PXRD and FTIR showed that Form I does not suffer phase change when submitted to controlled conditions of temperature and humidity. Moreover, HPLC and FTIR proved the chemical stability of this solid form of fosamprenavir, thus demonstrating its suitability for pharmaceutical purposes.


Assuntos
Carbamatos/química , Organofosfatos/química , Preparações Farmacêuticas/análise , Sulfonamidas/química , Tecnologia Farmacêutica/métodos , Furanos , Umidade , Microscopia Eletrônica de Varredura , Análise Espectral/métodos , Temperatura , Termodinâmica
14.
J Chromatogr A ; 1620: 461012, 2020 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-32276856

RESUMO

Quantification of analysis results for the suspect and non-targeted screening is essential for obtaining meaningful insight from the measurements. Ionization efficiency predictions is a possible approach to enable quantitation without standard substances. This is, however, especially challenging for the analysis carried out by combining the full scan mode either with fragmentation experiments in data-dependent or data-independent acquisition mode. Here we investigate the correlation of ionization efficiency values measured in full scan mode with the response factors measured in multiple reaction monitoring (MRM) mode for derivatized amino acids. We observe good correlation (R2 of 0.80) for 6-Aminoquinolyl-N-hydroxysuccinimidyl carbamate (AQC) derivatized amino acids. This encourages the use of the measured ionization efficiency values to estimate amino acid concentrations in different beverages. We apply the measured ionization efficiency values for estimating the concentration of amino acids for measurements done both in full scan as well as in MRM mode in wines and beers. We show that the calculated concentrations are in very good correlation with measured values (R2 of 0.71 to 1.00). The method possesses average trueness of 70.5% and shows an insignificant matrix effect.


Assuntos
Aminoácidos/análise , Cromatografia Líquida/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Vinho/análise , Aminas/análise , Aminoácidos/química , Aminoquinolinas/química , Cerveja/análise , Carbamatos/química , Indicadores e Reagentes , Malonatos/química , Reprodutibilidade dos Testes
15.
J Chromatogr A ; 1621: 461053, 2020 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-32276857

RESUMO

The chromatographic properties of a new coated amylose tris(3-chloro-5-methylphenylcarbamate) were evaluated in supercritical fluid chromatography for the separation of enantiomers of chiral 1-aryl-5-aryl-pyrrolidin-2-one derivatives, potential anticancer agents, and some commercial drugs. The mobile phase consisted of CO2-modifier mixtures with 30% of either methanol or ethanol, the flow rate was 3 mL/min. The column oven temperature was 40 °C and the outlet pressure was 15 MPa, in order to limit the compressibility of the CO2, thus limiting density variation along the column. The obtained results were then compared to those observed toward 3 other stationary phases: the coated amylose tris(3,5-dimethylphenylcarbamate), the immobilized amylose tris(3,5-dimethylphenylcarbamate) and the coated amylose tris(5-chloro-2-methylphenylcarbamate). It was shown that the new coated amylose tris(3-chloro-5-methylphenylcarbamate) was the most retentive column whatever the studied compounds, particularly for thalidomide and omeprazole with retention factors up to 73.3 and 29.5for the second enantiomer, respectively. Concerning the enantioselectivity, even most of the compounds are separated on all the four columns, the coated amylose tris(3-chloro-5-methylphenylcarbamate) allows the best resolution for most of the ten studied analytes (except omeprazole for which the resolution values are equal to 7.8 and 9.7 on the coated amylose tris(3-chloro-5-methylphenylcarbamate) and amylose tris(3,5-dimethylphenylcarbamate), respectively). Acting in complementary ways, the two chlorinated stationary phases permitted the complete separation of enantiomers of nine compounds out of the ten.


Assuntos
Amilose/análogos & derivados , Cromatografia com Fluido Supercrítico/métodos , Amilose/química , Antineoplásicos/análise , Antineoplásicos/isolamento & purificação , Carbamatos/química , Preparações Farmacêuticas/análise , Preparações Farmacêuticas/isolamento & purificação , Fenilcarbamatos/química , Pirrolidinonas/análise , Pirrolidinonas/isolamento & purificação , Dióxido de Silício/química , Estereoisomerismo
16.
Nat Chem Biol ; 16(6): 660-666, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32152543

RESUMO

Nitric oxide synthase 3 (NOS3) produces the gasotransmitter nitric oxide (NO), which drives critical cellular signaling pathways by S-nitrosylating target proteins. Endogenous NOS3 resides at two distinct subcellular locations: the plasma membrane and the trans-Golgi network (TGN). However, NO generation arising from the activities of both these pools of NOS3 and its relative contribution to physiology or disease is not yet resolvable. We describe a fluorescent DNA-based probe technology, NOckout, that can be targeted either to the plasma membrane or the TGN, where it can quantitatively map the activities of endogenous NOS3 at these locations in live cells. We found that, although NOS3 at the Golgi is tenfold less active than at the plasma membrane, its activity is essential for the structural integrity of the Golgi. The newfound ability to spatially map NOS3 activity provides a platform to discover selective regulators of the distinct pools of NOS3.


Assuntos
DNA/química , Corantes Fluorescentes/química , Óxido Nítrico Sintase Tipo III/metabolismo , Carbamatos/química , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Humanos , Cinética , Óxido Nítrico/metabolismo , Imagem Óptica , Polietilenoglicóis/química , Imagem Individual de Molécula , Rede trans-Golgi/metabolismo
17.
J Chromatogr A ; 1621: 461035, 2020 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-32188564

RESUMO

The present work described two triacontyl-bonded silica adsorbents containing different polar embedded groups (i.e. amide- and carbamate-type) for high performance liquid chromatography, which were prepared by covalent surface modification of silica gel with respective pre-synthesized polar-embedded triacontyl (C30) silane. The acylimidazole-mediated method was used for the first time for the synthesis of amide-type alkyl silane, while the carbamate-type silane was obtained via an improved solvent-free procedure. A conventional C30 stationary phase was also developed on the same silica substrate in the similar manner, which was used as a reference column for comparison of the unique mechanisms facilitated and/or furnished by the polar groups. The successful immobilization of the designed C30 species was confirmed by infrared spectroscopy and elemental analysis. In further comparison with an amide-embedded octadecyl (C18) two other conventional C18 stationary phases of different surface chemistry, detailed chromatographic characterization of the C30 series stationary phases was performed in terms of surface density, hydrophobicity, aromatic selectivity, shape selectivity and water tolerance using a diversified range of analytes, including homologous alkylbenzenes, isomeric polycyclic aromatic hydrocarbons, carotenes, congeners of polychlorobiphenyls, aromatic amines, phenolic compounds, estrogens and nucleosides. A high resemblance between the chromatographic behaviors of the two polar-modified C30 stationary phases was observed, meanwhile they demonstrated noticeable differences from non-polar C30 stationary phase. The polar-embedded C30 phases showed satisfactory performance towards the solutes of interest in the studied conditions. The beneficial synergy of the polar groups and the triacontyl chains enabled these polar-enhanced C30 stationary phases to address challenging separation tasks with high selectivity.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Dióxido de Silício/química , Amidas/química , Aminas/análise , Derivados de Benzeno/análise , Carbamatos/química , Carotenoides/análise , Estrogênios/análise , Interações Hidrofóbicas e Hidrofílicas , Nucleosídeos/análise , Fenóis/análise , Bifenilos Policlorados/análise , Hidrocarbonetos Policíclicos Aromáticos/análise , Silanos/química , Sílica Gel/química
18.
J Enzyme Inhib Med Chem ; 35(1): 629-638, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32037904

RESUMO

Phialophora verrucosa causes several fungal human diseases, mainly chromoblastomycosis, which is extremely difficult to treat. Several studies have shown that human immunodeficiency virus peptidase inhibitors (HIV-PIs) are attractive candidates for antifungal therapies. This work focused on studying the action of HIV-PIs on peptidase activity secreted by P. verrucosa and their effects on fungal proliferation and macrophage interaction. We detected a peptidase activity from P. verrucosa able to cleave albumin, sensitive to pepstatin A and HIV-PIs, especially lopinavir, ritonavir and amprenavir, showing for the first time that this fungus secretes aspartic-type peptidase. Furthermore, lopinavir, ritonavir and nelfinavir reduced the fungal growth, causing remarkable ultrastructural alterations. Lopinavir and ritonavir also affected the conidia-macrophage adhesion and macrophage killing. Interestingly, P. verrucosa had its growth inhibited by ritonavir combined with either itraconazole or ketoconazole. Collectively, our results support the antifungal action of HIV-PIs and their relevance as a possible alternative therapy for fungal infections.


Assuntos
Antifúngicos/farmacologia , Ácido Aspártico Proteases/antagonistas & inibidores , Inibidores da Protease de HIV/farmacologia , Macrófagos/efeitos dos fármacos , Phialophora/efeitos dos fármacos , Antifúngicos/síntese química , Antifúngicos/química , Ácido Aspártico Proteases/metabolismo , Carbamatos/síntese química , Carbamatos/química , Carbamatos/farmacologia , Relação Dose-Resposta a Droga , Furanos , Inibidores da Protease de HIV/síntese química , Inibidores da Protease de HIV/química , Humanos , Lopinavir/síntese química , Lopinavir/química , Lopinavir/farmacologia , Macrófagos/metabolismo , Testes de Sensibilidade Microbiana , Estrutura Molecular , Phialophora/enzimologia , Phialophora/crescimento & desenvolvimento , Ritonavir/síntese química , Ritonavir/química , Ritonavir/farmacologia , Relação Estrutura-Atividade , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia
19.
Phys Chem Chem Phys ; 22(8): 4464-4480, 2020 Feb 26.
Artigo em Inglês | MEDLINE | ID: mdl-32057044

RESUMO

Infection by human immunodeficiency virus type 1 (HIV-1) not only destroys the immune system bringing about acquired immune deficiency syndrome (AIDS), but also induces serious neurological diseases including behavioral abnormalities, motor dysfunction, toxoplasmosis, and HIV-1 associated dementia. The emergence of HIV-1 multidrug-resistant mutants has become a major problem in the therapy of patients with HIV-1 infection. Focusing on the wild type (WT) and G48T/L89M mutated forms of HIV-1 protease (HIV-1 PR) in complex with amprenavir (APV), indinavir (IDV), ritonavir (RTV), and nelfinavir (NFV), we have investigated the conformational dynamics and the resistance mechanism due to the G48T/L89M mutations by conducting a series of molecular dynamics (MD) simulations and free energy (MM-PBSA and solvated interaction energy (SIE)) analyses. The simulation results indicate that alterations in the side-chains of G48T/L89M mutated residues cause the inner active site to increase in volume and induce more curling of the flap tips, which provide the main contributions to weaker binding of inhibitors to the HIV-1 PR. The results of energy analysis reveal that the decrease in van der Waals interactions of inhibitors with the mutated PR relative to the wild-type (WT) PR mostly drives the drug resistance of mutations toward these four inhibitors. The energy decomposition analysis further indicates that the drug resistance of mutations can be mainly attributed to the change in van der Waals and electrostatic energy of some key residues (around Ala28/Ala28' and Ile50/Ile50'). Our work can give significant guidance to design a new generation of anti-AIDS inhibitors targeting PR in the therapy of patients with HIV-1 infection.


Assuntos
Protease de HIV/metabolismo , Simulação de Dinâmica Molecular , Fármacos Anti-HIV/química , Fármacos Anti-HIV/metabolismo , Carbamatos/química , Carbamatos/metabolismo , Resistência a Medicamentos/efeitos dos fármacos , Resistência a Medicamentos/genética , Furanos , Protease de HIV/genética , Indinavir/química , Indinavir/metabolismo , Conformação Molecular , Mutação , Nelfinavir/química , Nelfinavir/metabolismo , Ligação Proteica , Ritonavir/química , Ritonavir/metabolismo , Sulfonamidas/química , Sulfonamidas/metabolismo
20.
Molecules ; 25(4)2020 Feb 12.
Artigo em Inglês | MEDLINE | ID: mdl-32059495

RESUMO

We prepared a series of 10 carbamates derivatives based on two common antiprotozoal drugs: metronidazole (1-5) and secnidazole (6-10). The compounds were tested in vitro against a set of two amitochondriate protozoa: Giardia duodenalis and Trichomonas vaginalis. Compounds 1-10 showed strong antiprotozoal activities, with potency values in the low micromolar-to-nanomolar range, being more active than their parent drugs. Metronidazole carbamate (1) was the most active of the series, with nanomolar activities against G. duodenalis (IC50 = 460 nM) and T. vaginalis (IC50 = 60 nM). The potency of compound 1 was 10 times greater than that of metronidazole against both parasites. None of compounds showed in vitro cytotoxicity against VERO cells tested at 100 µM. Molecular dynamics of compounds 1-10, secnidazole, and metronidazole onto the ligand binding site of pyruvate-ferredoxin oxidoreductase of T. vaginalis and the modeled -tubulin of G. duodenalis revealed putative molecular interactions with key residues in the binding site of both proteins implicated in the mode of action of the parent drugs.


Assuntos
Antiprotozoários/farmacologia , Carbamatos/química , Metronidazol/análogos & derivados , Metronidazol/química , Antiprotozoários/síntese química , Antiprotozoários/química , Carbamatos/síntese química , Carbamatos/farmacologia , Giardia lamblia/efeitos dos fármacos , Giardia lamblia/patogenicidade , Giardíase/tratamento farmacológico , Giardíase/parasitologia , Metronidazol/síntese química , Metronidazol/farmacologia , Tricomoníase/tratamento farmacológico , Tricomoníase/parasitologia , Trichomonas vaginalis/efeitos dos fármacos , Trichomonas vaginalis/patogenicidade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...