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1.
Artigo em Inglês | MEDLINE | ID: mdl-31479387

RESUMO

An extraction method based on metal-organic framework has been developed and applied to acetanilide herbicides, including metazachlor, propanil, pretilachlor, and butachlor, in black beans, red beans, and kidney beans. The acetanilide herbicides are extracted with a mixture of ethyl acetate and n-hexane. The extract solution is absorbed and purified with metal-organic framework MIL-101 (Zn). The separation and determination of four acetanilide herbicides were implemented by high-performance liquid chromatography. The experimental parameters were evaluated by a univariate method and orthogonal experiments. The presented method can obtain effective extraction and purification. The detection limits for metazachlor, propanil, pretilachlor, and butachlor were 0.58, 0.90, 1.78 and 1.18 µg/kg, respectively. The average recoveries of the acetanilide herbicides at spiked concentrations of 10, 50, and 100 µg/kg ranged from 86.9% to 119.0%, and relative standard deviations were equal to or lower than 2.80%.


Assuntos
Acetanilidas/isolamento & purificação , Herbicidas/isolamento & purificação , Estruturas Metalorgânicas/química , Acetanilidas/química , Acetatos/química , Adsorção , Animais , Canavalia/química , Herbicidas/química , Hexanos/química , Tamanho da Partícula , Phaseolus/química
2.
Int J Nanomedicine ; 14: 3943-3953, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31239664

RESUMO

Background: SKLB023, a novel 5-benzylidenethiazolidine-2,4-dione based-derivative, specifically inhibits inducible nitric oxide synthase and shows promise for treating non-alcoholic steatohepatitis (NASH). However, its poor water solubility and low bioavailability limits its clinical use. Here the drug was loaded into phosphatidylcholine-bile salt-mixed micelles (PBMM/SKLB023) to overcome these limitations. Methods: PBMM/SKLB023 was developed using a simple co-precipitation method, and formulation parameters were optimized. The pharmacokinetics of PBMM/SKLB023 were investigated in Wistar rats, and therapeutic efficacy was assessed in a mouse model of NASH induced by a diet deficient in methionine- and choline. Results: PBMM/SKLB023 particles were 11.36±2.08 nm based on dynamic light scattering, and loading the drug into micelles improved its water solubility 300-fold. PBMM/SKLB023 inhibited proliferation and activation of HSC-T6 cells more strongly than free SKLB023. PBMM/SKLB023 showed longer mean retention time and higher bioavailability than the free drug after intravenous injection in Wistar rats. In the mouse model of NASH, PBMM/SKLB023 alleviated hepatic lipid accumulation, inflammation, and fibrosis to a significantly greater extent than free SKLB023. Conclusion: PBMM/SKLB023 shows therapeutic potential for treating NASH and liver fibrosis.


Assuntos
Acetanilidas/uso terapêutico , Micelas , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Tiazolidinedionas/uso terapêutico , Acetanilidas/sangue , Acetanilidas/química , Acetanilidas/farmacocinética , Animais , Ácidos e Sais Biliares/química , Modelos Animais de Doenças , Inflamação/patologia , Injeções Intravenosas , Cirrose Hepática/patologia , Masculino , Camundongos Endogâmicos C57BL , Fosfatidilcolinas/química , Ratos Wistar , Solubilidade , Tiazolidinedionas/sangue , Tiazolidinedionas/química , Tiazolidinedionas/farmacocinética
3.
Environ Sci Pollut Res Int ; 26(21): 21579-21588, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31127512

RESUMO

Polycaprolactone nanocapsules (PCL) containing pretilachlor were prepared, and Fourier transform infrared spectroscopy, atomic force microscopy, and transmission electron microscopy were used for their structural and morphological investigations. The results revealed that the nanocapsules had irregular shape and their particles size was in the range of 70-200 nm. The encapsulation efficiency of pretilachlor was measured as 99.5 ± 1.3% using high-performance liquid chromatography analysis. The physicochemical stability studies over 60 days showed that the nanocapsules were stable in the suspension without any aggregation. The herbicide activity was examined in a pre-emergence manner using barnyard grass as a target plant and rice as a non-target plant. The nanoformulation had no negative effect on rice plant. However, its effect on barnyard grass was significant. The cytotoxicity analysis indicated that the nanocapsulated herbicide is less toxic rather than the commercial formulation. Therefore, encapsulation of pretilachlor in PCL nanocapsules can be used effectively to construct environmentally friendly PCL-herbicide systems in agriculture.


Assuntos
Acetanilidas/química , Herbicidas/química , Nanocápsulas , Poliésteres/química , Microscopia de Força Atômica , Microscopia Eletrônica de Transmissão , Tamanho da Partícula , Espectroscopia de Infravermelho com Transformada de Fourier
4.
Arch Microbiol ; 201(6): 737-746, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30820617

RESUMO

Marine actinobacteria are less explored than their terrestrial counterparts as potential source of natural products. The present study was aimed to elucidate the bioactive potential of metabolites produced by marine-derived actinobacterial strain Streptomyces sp.SCA29 isolated from Havelock Island, Andaman and Nicobar Islands, India. The potential isolate SCA29 was identified as Streptomyces sp. by phenotypic, genotypic (16S-rRNA) and phylogenetic analyses. The crude bioactive compound was extracted using organic solvents. The compounds were subjected to separation and purification by column chromatography which yielded six fractions. Each fraction was assayed for inhibition of α-glucosidase and α-amylase enzymes, antagonistic activity against bacterial pathogens, and cytotoxic activity against various cell lines. The fraction F3c was considered to be highly active owing to its significant inhibition potential against α-glucosidase and α-amylase enzymes with IC50 values as 44.26 and 53.19 µg/mL, respectively. The active fraction showed antibacterial activity against test bacterial pathogens with the MIC value ranged from 3.90 to 31.25 µg/mL. The compound also exhibited concentration-dependent cytotoxicity on various cell lines without significant effect against human normal cells. The bioassay-guided fractionation of extract led to the identification of 4-methoxyacetanilide, an acetamide derivative. The structure of the bioactive compound was confirmed by HR-MS, NMR (1H and 13C) and FT-IR spectra, and by comparison with literature data.


Assuntos
Acetanilidas/isolamento & purificação , Acetanilidas/farmacologia , Antibacterianos/isolamento & purificação , Antibacterianos/farmacologia , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Streptomyces/metabolismo , Acetanilidas/química , Acetanilidas/metabolismo , Antibacterianos/química , Antibacterianos/metabolismo , Linhagem Celular , DNA Bacteriano/genética , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores de Glicosídeo Hidrolases/química , Inibidores de Glicosídeo Hidrolases/isolamento & purificação , Inibidores de Glicosídeo Hidrolases/metabolismo , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Índia , Filogenia , RNA Ribossômico 16S/genética , Espectroscopia de Infravermelho com Transformada de Fourier , Streptomyces/classificação , Streptomyces/genética , Streptomyces/isolamento & purificação , alfa-Amilases/antagonistas & inibidores , alfa-Amilases/química , alfa-Glucosidases/química
5.
J Pharm Biomed Anal ; 168: 181-188, 2019 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-30818256

RESUMO

During the related substances testing of mirabegron extended release tablets, an unknown peak was observed in HPLC chromatograms in a level exceeding the identification threshold. By using a strategy that combines LC-PDA/UV-MSn with mechanism-based stress studies, the unknown peak was rapidly identified as cyanomethyl mirabegron, a solution degradant that is caused by a Strecker-like reaction between the API, formaldehyde (an impurity in PEG), and HCN (an impurity in HPLC grade acetonitrile). The mechanism of the solution degradation chemistry was verified by stressing mirabegron with formaldehyde and trimethylsilyl cyanide (TMSCN, a synthetic reagent that generates HCN upon contact with water), in which the secondary amine group of mirabegron first reacts with formaldehyde to form the iminium ion intermediate; the latter then undergoes a nucleophilic attack by cyanide to yield the cyanomethyl mirabegron. The structure of the impurity was further confirmed through the synthesis of the impurity and subsequent structure characterization by 1D and 2D NMR. Due to the ubiquitous presence of formaldehyde in pharmaceutical excipients (e.g., PEG and polysorbate) and trace amount of HCN in HPLC grade acetonitrile, this type of solution degradation would likely occur in sample preparations of pharmaceutical finished products containing APIs with primary and secondary amine moieties. In a GMP environment, such an event may trigger undesirable out-of-specification (OOS) investigations; the results of this paper should help resolve such OOS investigations or even prevent these events from happening in the first place.


Assuntos
Acetanilidas/química , Agonistas de Receptores Adrenérgicos beta 3/química , Cromatografia Líquida de Alta Pressão/métodos , Excipientes/química , Tiazóis/química , Acetanilidas/normas , Acetonitrilos/química , Agonistas de Receptores Adrenérgicos beta 3/normas , Química Farmacêutica/métodos , Preparações de Ação Retardada , Formaldeído/química , Cianeto de Hidrogênio/química , Limite de Detecção , Espectroscopia de Ressonância Magnética/métodos , Espectrometria de Massas/métodos , Polietilenoglicóis/química , Comprimidos , Tiazóis/normas
6.
J Environ Sci Health B ; 54(4): 303-312, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30638119

RESUMO

The rice straw ash (RSA) and wheat straw ash (WSA) were explored as low cost adsorbent for pretilachlor removal from water. The ashes were characterized and sorption behavior of pretilachlor was evaluated. Kinetics study suggested that the modified Elovich model best explained the pretilachlor sorption on both the ashes. The adsorption data were analyzed using 2-, 3- and 4-parameter models and nine error functions were used to compute the best fit isotherm by nonlinear regression analysis. The pretilachlor was more sorbed onto the RSA (22.0-92.2%) than the WSA (11.4-61.4%) and percent adsorption decreased with increase in the herbicide concentration in solution. Isotherm model optimization analysis suggested that the Freundlich and the Temkin isotherms were the best models to predict the pretilachlor adsorption onto the RSA and the WSA. The error analysis suggested that the reciprocal of the observed squared (ROS) and the reciprocal of the predicted squared (RPS) error functions provided the best determination of the adsorption constants for the Freundlich and the Temkin isotherms, respectively. The RSA, which exhibited higher pretilachlor sorption potential, can be utilized as low cost adsorbent for pesticide removal from contaminated water.


Assuntos
Acetanilidas/isolamento & purificação , Herbicidas/isolamento & purificação , Oryza , Triticum , Poluentes Químicos da Água/isolamento & purificação , Acetanilidas/química , Adsorção , Herbicidas/química , Cinética , Modelos Químicos , Caules de Planta , Análise de Regressão , Poluentes Químicos da Água/química
7.
Molecules ; 23(12)2018 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-30558193

RESUMO

It has been established that an electron-deficient cationic CpE-rhodium(III) complex catalyzes the non-oxidative [2+2+2] annulation of N-(1-naphthyl)acetamide with two alkynoates via cleavage of the adjacent C⁻H and C⁻N bonds to give densely substituted phenanthrenes under mild conditions (at 40 °C under air). In this reaction, a dearomatized spiro compound was isolated, which may support the formation of a cationic spiro rhodacycle intermediate in the catalytic cycle. The use of N-(1-naphthyl)acetamide in place of acetanilide switched the reaction pathway from the oxidative [2+2+2] annulation-lactamization via C⁻H/C⁻H cleavage to the non-oxidative [2+2+2] annulation via C⁻H/C⁻N cleavage. This chemoselectivity switch may arise from stabilization of the carbocation in the above cationic spiro rhodacycle by the neighboring phenyl and acetylamino groups, resulting in the nucleophilic C⁻C bond formation followed by ß-nitrogen elimination.


Assuntos
Acetamidas/química , Ródio/química , Acetanilidas/química , Elétrons , Estrutura Molecular
8.
J Agric Food Chem ; 66(46): 12198-12205, 2018 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-30376318

RESUMO

A water-soluble inclusion complex for butachlor was prepared by complexation with (2-hydroxypropyl)-ß-cyclodextrin (HP-ß-CD). Phase solubility results indicated a 1:1 stoichiometric ratio with an apparent stability constant of 864.3 M-1 in the obtained solid complex. The formation of the complex was confirmed by 1H nuclear magnetic resonance, Fourier transform infrared, and differential scanning calorimetry spectra. Coupled with the molecular docking results, butachlor was considered to be completely included in HP-ß-CD cavity. Butachlor complexation with HP-ß-CD decreased its adsorption capacity and enhanced its mobility in soil. The inclusion complex displayed better herbicidal activities than free butachlor. The 96 h median lethal concentration values of the inclusion complex and free butachlor was 2.30 and 0.65 mg L-1, respectively, for zebrafish, indicating that the complexation could significantly reduce toxicity to fishes. The present study provides an approach to develop environment-friendly formulations using CDs for herbicides.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Acetanilidas/química , Herbicidas/química , Acetanilidas/toxicidade , Animais , Bioensaio , Portadores de Fármacos/química , Herbicidas/toxicidade , Concentração de Íons de Hidrogênio , Espectroscopia de Ressonância Magnética , Solo/química , Solubilidade , Peixe-Zebra
9.
Ecotoxicol Environ Saf ; 161: 145-155, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-29879575

RESUMO

Understanding and quantifying the adsorption-desorption behaviour of herbicide in soil is imperative for predicting their fate and transport in the environment. In the present study, the effect of time and temperature on the adsorption-desorption behaviour of pretilachlor in soils was investigated using batch equilibration technique. The adsorption-desorption kinetics of pretilachlor in soils was two step process and was well described by pseudo-second-order kinetic model. Freundlich model accurately predicted the sorption behaviour of pretilachlor. The adsorption-desorption of pretilachlor varied significantly with the concentration, temperature and properties of soil viz. organic matter and clay content. All the studied soils had non-linear slopes (n < 1) and degree of nonlinearity increased with increase in clay, organic matter content and temperature (p < 0.05). Desorption of pretilachlor was hysteretic in studied soils and hysteresis coefficient varied from 0.023 to 0.275. Thermodynamic analysis showed that pretilachlor adsorption onto soils was a feasible, spontaneous and endothermic process which becomes more favourable at high temperature. It could be inferred that the adsorption of pretilachlor on soils was physical in nature.


Assuntos
Acetanilidas/química , Herbicidas/química , Poluentes do Solo/química , Solo/química , Temperatura Ambiente , Adsorção , Argila , Substâncias Húmicas , Cinética , Plantas , Termodinâmica
10.
ACS Chem Biol ; 13(8): 1932-1937, 2018 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-29851463

RESUMO

Mapping proteins at a specific subcellular location is essential to gaining detailed insight on local protein dynamics. We have developed an enzymatic strategy to label proteins on a subcellular level using arylamine N-acetyltransferase (NAT). The NAT enzyme activates an arylhydroxamic acid functionality into a nitrenium ion that reacts fast, covalently, and under neutral conditions with nucleophilic residues of neighboring proteins. The electron density on the aromatic ring proved important for probe activation as strong labeling was only observed with an arylhydroxamic acid bearing an electron donating substituent. We further demonstrate that, using this electron rich arylhydroxamic acid, clear labeling was achieved on a subcellular level in living cells that were transfected with a genetically targeted NAT to the nucleus or the cytosol.


Assuntos
Acetanilidas/química , Arilamina N-Acetiltransferase/química , Ácidos Hidroxâmicos/química , Isoenzimas/química , Sondas Moleculares/química , Proteínas/metabolismo , Acetanilidas/síntese química , Arilamina N-Acetiltransferase/metabolismo , Núcleo Celular/metabolismo , Citosol/metabolismo , Células HEK293 , Humanos , Ácidos Hidroxâmicos/síntese química , Isoenzimas/metabolismo , Sondas Moleculares/síntese química , Sinais de Localização Nuclear , Proteômica/métodos
11.
Bull Environ Contam Toxicol ; 100(6): 856-861, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29671016

RESUMO

This study was conducted at ambient (398 ± 10 µmol mol-1), elevated (450 ± 10 µmol mol-1) and elevated (550 ± 10 µmol mol-1) atmospheric CO2 under three moisture regime and also three level of temperature (4, 25, and 40°C) to assess the degradation of pretilachlor and butachlor. Under dry condition at 398 ± 10 µmol mol-1, T1/2 was 28.5 and 59.4 days for pretilachlor and butachlor, respectively; slowly decreased to 18.2 and 44.5 days at 550 ± 10 µmol mol-1 indicated that elevated condition enhanced degradation than ambient condition. Under field capacity with increasing CO2 levels from ambient to elevated, T1/2 decreased from 18.9 to 11.6 days and 39.4 to 16.2 days for of pretilachlor and butachlor, respectively. Similarly, under submerged conditions with increasing CO2 levels T1/2 decreased 14.7-7.1 and 26.3-11.8 days for pretilachlor and butachlor, respectively. Study also revealed that both pretilachlor and butachlor dissipated faster at 40°C (T1/2, 9.7 and 19.4 days) than 25°C (T1/2, 16.2 and 36.7 days). Slower dissipation was recorded at 4°C (T1/2, 87.6 and 182.4 days).


Assuntos
Acetanilidas/análise , Dióxido de Carbono/química , Solo/química , Acetanilidas/química , Dióxido de Carbono/metabolismo , Temperatura Ambiente
12.
J Environ Manage ; 217: 592-599, 2018 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-29649731

RESUMO

The use of treated wastewaters (TWW) in agriculture is widening in areas suffering drought, such as southern Europe, to preserve freshwater supply for human consumption. The composition of TWW, especially concerning their organic carbon (OC) content, has been demonstrated to influence the processes governing the behavior of non-ionic pesticides in soils. Three OC-poor agricultural soils (SV, RM1 and RM3) from the province of Granada (Spain) were chosen for the assessment of the adsorption and desorption of the herbicide dimethenamid (DIM) and the fungicide fenarimol (FEN). TWW and sewage sludge extracts at different dissolved OC (DOC) concentrations (30, 90 and 300 mg L-1) were considered to evaluate their effect on pesticide adsorption-desorption. As expected by their properties, DIM and FEN were weakly and moderately adsorbed to the soils, respectively. Soil OC seemed to be the major factor controlling FEN adsorption, whereas the mineral fraction played a key role in DIM adsorption, especially in RM1 with high clay:OC ratio. Although TWW did not significantly modify the adsorption of pesticides, it enhanced DIM desorption from the three soils. Adsorption of FEN to SV and RM3 was directly related to the concentration of DOC, possibly due to co-sorption phenomena. Hysteretic desorption was found in all cases, indicating partially reversible adsorption. While FEN desorption was not altered by the solutions, the use of sludge extracts at the highest DOC concentration (300 mg L-1) enhanced DIM desorption as occurred with TWW. Interactions with DOC in solution seemed to predominate for this less hydrophobic compound, thus increasing the risk of natural waters contamination if TWW will be used.


Assuntos
Acetanilidas/química , Pirimidinas/química , Águas Residuárias , Acetanilidas/isolamento & purificação , Adsorção , Carbono , Europa (Continente) , Humanos , Pirimidinas/isolamento & purificação , Esgotos , Solo , Poluentes do Solo , Espanha
13.
J Chromatogr A ; 1552: 43-52, 2018 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-29650481

RESUMO

Hydrogen sulfide (H2S), previously known as a toxic gas, is now recognized as a gasotransmitter along with nitric oxide and carbon monoxide. However, only few methods are available for quantitative determination of H2S in biological samples. 2-Iodoacetanilide (2-IAN), a thiol-reacting agent, has been used to tag the reduced cysteine residues of proteins for quantitative proteomics and for detection of cysteine oxidation modification. In this article, we proposed a new method for quantitative analyses of H2S and thiol metabolites using the procedure of pre-column 2-IAN derivatization coupled with liquid chromatography-electrospray ionization-mass spectrometry (LC-ESI-MS). 13C6-Labeled and label-free 2-IAN efficiently react with H2S and thiol compounds at pH 9.5 and 65 °C. The derivatives exhibit excellent stability at alkaline conditions, high resolution on reverse phase liquid chromatography and great sensitivity for ESI-MS detection. The measurement of H2S, l-cysteine, glutathione, and DL-homocysteine derivatives was validated using 13C6-labeled standard in LC-ESI-MS analyses and exhibited 10 nM-1 µM linear ranges for DL-homocysteine and glutathione and 1 nM-1 µM linear ranges for l-cysteine and H2S. In addition, the sequence of derivatization and extraction of metabolites is important in the quantification of thiol metabolites suggesting the presence of matrix effects. Most importantly, labeling with 2-IAN and 13C6-2-IAN isotopologues could achieve quantitative and matched sample comparative analyses with minimal bias using our extraction and labeling procedures before LC-MS analysis.


Assuntos
Acetanilidas/química , Sulfeto de Hidrogênio/análise , Espectrometria de Massas por Ionização por Electrospray , Compostos de Sulfidrila/análise , Isótopos de Carbono/química , Cromatografia Líquida de Alta Pressão , Cisteína/análise , Glutationa/análise , Células Hep G2 , Homocisteína/análise , Humanos , Sulfeto de Hidrogênio/metabolismo , Marcação por Isótopo , Compostos de Sulfidrila/metabolismo
14.
Chem Commun (Camb) ; 54(27): 3387-3390, 2018 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-29553154

RESUMO

Amide bond formation has considerable significance in synthetic chemistry. Although the C-acyltransferase from Pseudomonas protegens has been found to catalyze C-C bond formation in nature as well as in in vitro experiments with non-natural substrates, it is now shown that the enzyme is also able to catalyze amide formation using aniline derivatives as substrates with promiscuous activity. Importantly, the amide formation was enabled in aqueous buffer. Identifying phenyl acetate as the most suitable acetyl donor, the products were obtained with up to >99% conversion and up to 99% isolated yield.


Assuntos
Acetanilidas/metabolismo , Aciltransferases/metabolismo , Pseudomonas/enzimologia , Acetanilidas/química , Biocatálise , Tampões (Química) , Água/química , Água/metabolismo
15.
Food Chem ; 245: 1190-1195, 2018 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-29287341

RESUMO

Ionic liquid-based matrix solid phase dispersion-solvent flotation coupled with high performance liquid chromatography was developed for the determination of the acetanilide herbicides, including metazachlor, propanil, alachlor, propisochlor, pretilachlor, and butachlor in rice samples. Some experimental parameters, including the type of dispersant, the mass ratio of dispersant to sample, pH of sample solution, the type of extraction solvent, the type of ionic liquid, flotation time, and flow rate of N2 were optimized. The average recoveries of the acetanilide herbicides at spiked concentrations of 50, 125, and 250 µg/kg ranged from 89.4% to 108.7%, and relative standard deviations were equal to or lower than 7.1%, the limits of quantification were in the range of 38.0 to 84.7 µg/kg.


Assuntos
Acetanilidas/isolamento & purificação , Contaminação de Alimentos/análise , Herbicidas/análise , Oryza/química , Extração em Fase Sólida/métodos , Acetamidas/análise , Acetanilidas/análise , Acetanilidas/química , Cromatografia Líquida de Alta Pressão/métodos , Líquidos Iônicos/química , Reprodutibilidade dos Testes , Solventes/química
16.
Phys Chem Chem Phys ; 19(33): 22564-22572, 2017 Aug 23.
Artigo em Inglês | MEDLINE | ID: mdl-28809963

RESUMO

Most proteins work in aqueous solution and the interaction with water strongly affects their structure and function. However, experimentally the motion of a specific single water molecule is difficult to trace by conventional methods, because they average over the heterogeneous solvation structure of bulk water surrounding the protein. Here, we provide a detailed atomistic picture of the water rearrangement dynamics around the -CONH- peptide linkage in the two model systems formanilide and acetanilide, which simply differ by the presence of a methyl group at the peptide linkage. The combination of picosecond pump-probe time-resolved infrared spectroscopy and molecular dynamics simulations demonstrates that the solvation dynamics at the molecular level is strongly influenced by this small structural difference. The effective timescales for solvent migration triggered by ionization are mainly controlled by the efficiency of the kinetic energy redistribution rather than the shape of the potential energy surface. This approach provides a fundamental understanding of protein hydration and may help to design functional molecules in solution with tailored properties.


Assuntos
Peptídeos/química , Solventes/química , Acetanilidas/química , Formamidas/química , Ligações de Hidrogênio , Simulação de Dinâmica Molecular , Peptídeos/metabolismo , Espectrofotometria Infravermelho , Água/química
17.
J Med Chem ; 60(14): 6289-6304, 2017 07 27.
Artigo em Inglês | MEDLINE | ID: mdl-28650658

RESUMO

PRMT5 plays important roles in diverse cellular processes and is upregulated in several human malignancies. Besides, PRMT5 has been validated as an anticancer target in mantle cell lymphoma. In this study, we found a potent and selective PRMT5 inhibitor by performing structure-based virtual screening and hit optimization. The identified compound 17 (IC50 = 0.33 µM) exhibited a broad selectivity against a panel of other methyltransferases. The direct binding of 17 to PRMT5 was validated by surface plasmon resonance experiments, with a Kd of 0.987 µM. Kinetic experiments indicated that 17 was a SAM competitive inhibitor other than the substrate. In addition, 17 showed selective antiproliferative effects against MV4-11 cells, and further studies indicated that the mechanism of cellular antitumor activity was due to the inhibition of PRMT5 mediated SmD3 methylation. 17 may represent a promising lead compound to understand more about PRMT5 and potentially assist the development of treatments for leukemia indications.


Assuntos
Acetanilidas/química , Antineoplásicos/química , Benzimidazóis/química , Proteína-Arginina N-Metiltransferases/antagonistas & inibidores , Acetanilidas/síntese química , Acetanilidas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzimidazóis/síntese química , Benzimidazóis/farmacologia , Linhagem Celular , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Bases de Dados de Compostos Químicos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Cinética , Leucemia , Linfoma , Metilação , Modelos Moleculares , Simulação de Acoplamento Molecular , Ligação Proteica , Proteína-Arginina N-Metiltransferases/química , Proteína-Arginina N-Metiltransferases/metabolismo , Relação Estrutura-Atividade , Proteínas Centrais de snRNP/metabolismo
18.
Eur J Med Chem ; 136: 382-392, 2017 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-28525839

RESUMO

Reduction of hippocampal neurogenesis caused by aging and neurological disorders would impair neural circuits and result in memory loss. A new lead compound (N-trans-3',4'-methylenedioxystilben-4-yl acetamide 27) has been discovered to efficiently stimulate adult rats' neurogenesis. In-depth structure-activity relationship studies proved the necessity of a stilbene scaffold that is absent in highly cytotoxic analogs such as chalcones and heteroaryl rings and inactive analogs such as diphenyl acetylene and diphenyl ethane, and validated the importance of an NH in the carboxamide and a methylenedioxy substituent on the benzene ring. Immunohistochemical staining and biochemical analysis indicate, in contrast to previously reported neuroprotective chemicals, N-stilbenyl carboxamides have extra capacity for neuroproliferation-type neurogenesis, thereby providing a foundation for improving the plasticity of the adult mammalian brain.


Assuntos
Acetanilidas/farmacologia , Descoberta de Drogas , Hipocampo/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Extratos Vegetais/química , Estilbenos/farmacologia , Acetanilidas/química , Acetanilidas/isolamento & purificação , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Humanos , Masculino , Estrutura Molecular , Ratos , Ratos Sprague-Dawley , Estilbenos/química , Estilbenos/isolamento & purificação , Relação Estrutura-Atividade
19.
Chem Pharm Bull (Tokyo) ; 65(5): 478-486, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28458369

RESUMO

Fixed dose combination tablets consisting of mirabegron (MB) and solifenacin succinate (SS) were developed and formulated into bilayer tablets in the current study. The results of a chemical stability study showed that the original formulation for the tablets led to a significant increase of unknown degradants in the SS layer. Two compatibility studies were conducted to simulate the interface between the MB and SS layers, and the results revealed that the degradants only formed in the presence of both active pharmaceutical ingredients (APIs), and that the presence of maltose in the SS layer was critical to inducing degradation. High resolution mass spectroscopy coupled with high performance liquid chromatography was used to determine the chemical structures of the degradants, which were identified to MB derivatives bearing one or two sugar units. These findings therefore suggested that the degradation of the API could be attributed to the addition of sugar units from maltose to MB under the acidic conditions caused by SS. With this in mind, we developed a new formulation by replacing maltose with hydroxypropyl cellulose as a polymer-type binder. The results showed that this formulation suppressed the formation of the degradants. The results of this study have shown that chemical degradation can occur at the interface of bilayer tablets and that an alternative strategy is available to formulate more stable MB/SS bilayer tablets.


Assuntos
Acetanilidas/química , Maltose/química , Succinato de Solifenacina/química , Tiazóis/química , Estabilidade de Medicamentos , Estrutura Molecular , Comprimidos/química
20.
ACS Infect Dis ; 3(5): 330-335, 2017 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-28301927

RESUMO

Influenza A virus envelop protein hemagglutinin (HA) plays important roles in viral entry. We previously have reported that MBX2546, a novel influenza A virus inhibitor, binds to HA and inhibits HA-mediated membrane fusion. In this report, we show that (i) both binding and stabilization of HA by MBX2546 are required for the inhibition of viral infection and (ii) the binding of HA by MBX2546 represses the low-pH-induced conformational change in the HA, which is a prerequisite for membrane fusion. Mutations in MBX2546-resistant influenza A/PR/8/34 (H1N1) viruses are mapped in the HA stem region near the amino terminus of HA2. Finally, we have modeled the binding site of MBX2546 using molecular dynamics and find that the resulting structure is in good agreement with our results. Together, these studies underscore the importance of the HA stem loop region as a potential target for therapeutic intervention.


Assuntos
Acetanilidas/química , Antivirais/química , Glicoproteínas de Hemaglutininação de Vírus da Influenza/química , Vírus da Influenza A Subtipo H1N1/química , Fusão de Membrana/efeitos dos fármacos , Sulfonamidas/química , Motivos de Aminoácidos , Animais , Sítios de Ligação , Bioensaio , Cães , Farmacorresistência Viral/fisiologia , Glicoproteínas de Hemaglutininação de Vírus da Influenza/metabolismo , Concentração de Íons de Hidrogênio , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Vírus da Influenza A Subtipo H1N1/metabolismo , Cinética , Células Madin Darby de Rim Canino , Simulação de Dinâmica Molecular , Ressonância Magnética Nuclear Biomolecular , Ligação Proteica , Conformação Proteica em alfa-Hélice , Conformação Proteica em Folha beta , Domínios e Motivos de Interação entre Proteínas , Multimerização Proteica , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo
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