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1.
J Agric Food Chem ; 67(42): 11710-11717, 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31600058

RESUMO

Lactuca sativa L. var. augustana has a basmati rice-like odor with a green note in the background. This typical odor is due to the release of 2-acetyl-1-pyrroline (2-AP) after heating, which is confirmed by volatile analysis. Recent metabolomic and genomic studies of different rice varieties highlighted that the presence of 2-AP was linked to the accumulation of γ-aminobutyraldehyde; genome-wide association studies also indicated that acyltransferases were involved. These results prompted us to analyze nonvolatile compound precursors in L. sativa L. var. augustana (celtuce) to search for compound derivatives with a 4,5-dioxohexan alkyl amine-like structure. Hypothetical synthetic compounds were prepared from a reductive amination between 4,5-dioxohexanal and glycine, alanine, aspartic acid, and glutamic acid to give 2-(2-acetylpyrrolidin-1-yl) alkanoic acid. We proved that 2-(2-acetylpyrrolidin-1-yl) propionic acid is present in L. sativa, which, when thermally treated, released 2-AP. Other 2-AP precursors occurring in this plant are discussed.


Assuntos
Alface/química , Extratos Vegetais/química , Pirróis/química , Genoma de Planta , Alface/genética , Espectrometria de Massas , Odorantes/análise
2.
J Chromatogr A ; 1604: 460478, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31474467

RESUMO

In this study, fabrication of a stir bar sorbent is presented by electropolymerization of pyrrole via cyclic voltametry for the first time. The fabricated stir bar was applied as an efficient sorbent for extraction and pre-concentration of trace amounts of estradiol in urine samples through stir bar sorptive extraction (SBSE) method followed by gas chromatography-flame ionization detector. For this purpose, first the surface of stainless steel rod was modified by hyroxide functional group. Then electropolymerization of pyrrole monomers took place on the surface of functionalized steel rod under the optimized conditions including pyrrole concentration of 0.03 mol L-1, equal concentration ratio of pyrrole to sodium dodecyl sulfate, 10 cycles of cyclic voltammetry and potential scan rate of 10 mV s-1. Characterization of the produced sorbent was confirmed by scanning electron microscope imaging and energy-dispersive X-ray and infrared spectroscopy. Evantually, under the optimized conditions, the stir bar sorbent was used for extraction of estradiol from human urine samples. The presented SBSE method showed a good linearity range of 50-700 ng mL-1 with coefficient of determination 0.9910, limit of detection 10 ng mL-1 and theoretical limit of quantification 33 ng mL-1. Moreover, better enrichment factor (87) and extraction recovery (43%) were obtained using the fabricated stir bar compared with two commercial stir bars for estradiol. The intra- and inter-bar relative recoveries were obtained 92.0% and their coefficient of variations were less than 5.4%.


Assuntos
Cromatografia Gasosa/métodos , Eletroquímica/métodos , Estradiol/isolamento & purificação , Polimerização , Pirróis/química , Eletrodos , Humanos , Concentração de Íons de Hidrogênio , Padrões de Referência , Reprodutibilidade dos Testes , Fatores de Tempo
3.
Inorg Chem ; 58(18): 12422-12432, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31483641

RESUMO

Fluorescence imaging is a powerful tool in biomedical research. It has been frequently used to uncover or better understand physiological mechanisms in disease-related processes such as cancer. The majority of chromophores used for imaging are based on a 4,4-difluoro-4-bora-3a,4a-diaza-s-indacene (BODIPY) scaffold. However, their applications are limited due to their poor water solubility as well as poor cancer cell selectivity. To circumvent these drawbacks, we present herein the use of bis(dipyrrinato)zinc(II) complexes. As this class of compounds is associated with a quenching effect of the excited state in water, the lead compound of this study (3) was encapsulated in a polymer matrix with biotin as a targeting moiety (3-NP). This encapsulation improved the water solubility, overcame the quenching effects in water, as well as allowed selective accumulation in the lysosomes with a bright fluorescence signal in monolayer cells as well as 3D multicellular tumor spheroids (MCTS). As a benefit from the biotin targeting moiety, the nanoparticles were majorly taken up by the sodium dependent multivitamin transporter (SMVT) which is overexpressed in various cancers cells and selectively accumulated in cancerous cells over noncancerous cells.


Assuntos
Corantes Fluorescentes/química , Lisossomos/patologia , Nanopartículas/química , Neoplasias/patologia , Polímeros/química , Pirróis/química , Zinco/química , Células A549 , Linhagem Celular , Complexos de Coordenação/química , Células HeLa , Humanos , Lisossomos/ultraestrutura , Microscopia Confocal/métodos , Neoplasias/diagnóstico por imagem , Imagem Óptica/métodos
4.
Chem Commun (Camb) ; 55(67): 10023-10026, 2019 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-31378804

RESUMO

Inspired by the formation mechanism of a biological membrane potential, we described the generation of an artificial membrane potential through redox-regulating anion distribution on the two sides of a polypyrrole film. The polarity of the membrane potential could be regulated by the redox reaction.


Assuntos
Materiais Biomiméticos/química , Polímeros/química , Pirróis/química , Técnicas Eletroquímicas , Potenciais da Membrana , Membranas Artificiais , Oxirredução
5.
Chem Commun (Camb) ; 55(66): 9833-9836, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31363722

RESUMO

Herein, through using electropolymerized pyrrole (PPy) to coat near-infrared upconversion nanoparticles (UCNPs) on an indium tin oxide (ITO) electrode, the as-prepared PPy/UCNPs photoelectrode could generate an interfacial electric field, release rare earth ions and induce reactive oxygen species (ROS) in PC12 cells under NIR irradiation, which could realize wireless neurite development and outgrowth.


Assuntos
Estimulação Elétrica , Crescimento Neuronal , Tecnologia sem Fio , Animais , Raios Infravermelhos , Células PC12 , Polimerização , Pirróis/química , Ratos , Espectrofotometria Ultravioleta
6.
Chem Commun (Camb) ; 55(66): 9829-9832, 2019 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-31363730

RESUMO

Polyethylene glycol grafted pyrrole-based conjugated polymers are synthesized through a one-pot multicomponent methodology, the self-assemblies of which enable nanoparticle size-selective encapsulation of drug molecules and their sustained release. Efficient loading of curcumin through drug-nanoparticle core interactions is probed using FRET, and the inherently fluorescent nature of polypyrrole could be used to detect these nanocarriers intracellularly.


Assuntos
Portadores de Fármacos , Nanopartículas/química , Polietilenoglicóis/química , Polímeros/química , Pirróis/química , Linhagem Celular Tumoral , Curcumina/administração & dosagem , Transferência Ressonante de Energia de Fluorescência , Humanos , Interações Hidrofóbicas e Hidrofílicas , Concentração Inibidora 50 , Microscopia Eletrônica de Transmissão , Espectrofotometria Ultravioleta
7.
Curr Top Med Chem ; 19(18): 1650-1675, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31424369

RESUMO

Human immunodeficiency virus type-1 (HIV-1) is the causative agent responsible for the acquired immunodeficiency syndrome (AIDS) pandemic. More than 60 million infections and 25 million deaths have occurred since AIDS was first identified in the early 1980s. Advances in available therapeutics, in particular combination antiretroviral therapy, have significantly improved the treatment of HIV infection and have facilitated the shift from high mortality and morbidity to that of a manageable chronic disease. Unfortunately, none of the currently available drugs are curative of HIV. To deal with the rapid emergence of drug resistance, off-target effects, and the overall difficulty of eradicating the virus, an urgent need exists to develop new drugs, especially against targets critically important for the HIV-1 life cycle. Viral entry, which involves the interaction of the surface envelope glycoprotein, gp120, with the cellular receptor, CD4, is the first step of HIV-1 infection. Gp120 has been validated as an attractive target for anti-HIV-1 drug design or novel HIV detection tools. Several small molecule gp120 antagonists are currently under investigation as potential entry inhibitors. Pyrrole, piperazine, triazole, pyrazolinone, oxalamide, and piperidine derivatives, among others, have been investigated as gp120 antagonist candidates. Herein, we discuss the current state of research with respect to the design, synthesis and biological evaluation of oxalamide derivatives and five-membered heterocycles, namely, the pyrrole-containing small molecule as inhibitors of gp120 and HIV entry.


Assuntos
Amidas/farmacologia , Fármacos Anti-HIV/farmacologia , Proteína gp120 do Envelope de HIV/antagonistas & inibidores , Inibidores da Fusão de HIV/farmacologia , Pirróis/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Amidas/química , Fármacos Anti-HIV/química , Descoberta de Drogas , Proteína gp120 do Envelope de HIV/metabolismo , Inibidores da Fusão de HIV/química , Infecções por HIV/tratamento farmacológico , HIV-1/efeitos dos fármacos , Humanos , Pirróis/química , Bibliotecas de Moléculas Pequenas/química
8.
Chem Commun (Camb) ; 55(73): 10920-10923, 2019 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-31441463

RESUMO

The development of new NIR-II fluorophores, particularly those with facile syntheses, high fluorescence quantum yields, and stable and tunable photophysical properties, is challenging. Herein, we report a new class of small molecular NIR-II fluorophores based on aza-dipyrromethene boron difluoride (aza-BODIPY) dyes. We demonstrate promising photophysical properties of these dyes, such as large Stokes shift, superior photostability, and good fluorescence brightness as nanoparticles in aqueous solution. Because of these properties and high resolution and deep penetration NIR-II imaging ability, the aza-BODIPY based dyes show great potential as NIR-II imaging agents.


Assuntos
Compostos de Boro/química , Corantes Fluorescentes/química , Imagem Óptica/métodos , Pirróis/química , Animais , Compostos de Boro/síntese química , Compostos de Boro/efeitos da radiação , Compostos de Boro/toxicidade , Linhagem Celular Tumoral , Teoria da Densidade Funcional , Desenho de Drogas , Fluorescência , Corantes Fluorescentes/síntese química , Corantes Fluorescentes/efeitos da radiação , Corantes Fluorescentes/toxicidade , Raios Infravermelhos , Camundongos , Modelos Químicos , Nanopartículas/química , Poloxâmero/química , Pirróis/síntese química , Pirróis/efeitos da radiação , Pirróis/toxicidade
10.
Inorg Chem ; 58(14): 9067-9075, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31268715

RESUMO

The binuclear platinum(II) boron-dipyrromethene (BODIPY) complex [{Pt(dach)}2(µ-Dcrb)] (DP), where dach is 1,2-diaminocyclohexane and H4Dcrb is a morpholine-conjugated BODIPY-linked dicatechol bridging ligand, was prepared for lysosome organelle targeting and near-IR (NIR) light (600-720 nm) induced photocytotoxic activity. The platinum complex [Pt(dach)(cat)] (CP), where H2cat is catechol, was synthesized and used as a control complex without bearing the BODIPY unit. The complex DP displayed a band at 660 nm (ε = 2.1 × 104 M-1 cm-1) in the red region of the UV-visible spectrum recorded in 10% dimethyl sulfoxide/Dulbecco's Modified Eagle's Medium (DMSO/DMEM, pH 7.2). The complex DP and the BODIPY ligand displayed emission in 10% DMSO-DMEM (pH 7.2) giving an λem value of 668 nm (λex = 650 nm) with a ΦF value of 0.02 for DP and 0.16 for H4Dcrb (ΦF, fluorescence quantum yield). Titration experiments using 1,3-diphenylisobenzofuran (DPBF) indicated that the complex DP and H4Dcrb on irradiation with near-IR light of 600-720 nm generated singlet oxygen (1O2) as the ROS (reactive oxygen species). The complex DP showed significant lysosomal localization and remarkable apoptotic photodynamic therapy (PDT) effects, giving half-maximal inhibitory concentration values (IC50) within 0.6-3.4 µM in HeLa cervical cancer, A549 lung cancer, and MDA-MB231 multidrug resistant cancer cells, while being essentially nontoxic in the dark and in the HPL1D immortalized lung epithelial normal cells. The acridine orange assay using A549 cells showed lysosomal membrane permeabilization by the complex DP under near-IR light (600-720 nm). This complex on near-IR light (600-720 nm) activation in A549 cells induced apoptotic cell death, as observed from an Annexin-V FITC assay.


Assuntos
Compostos de Boro/química , Lisossomos/química , Fotoquimioterapia , Compostos de Platina/química , Pirróis/química , Compostos de Boro/farmacologia , Linhagem Celular Tumoral , Cristalografia por Raios X , Humanos , Potenciais da Membrana/efeitos dos fármacos , Estrutura Molecular , Compostos de Platina/farmacologia
11.
Bioelectrochemistry ; 130: 107327, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31351314

RESUMO

A sensitive electrochemical detection of xanthine (X), which is an early biomarker of fish meat spoilage, was achieved by a novel biosensor developed via three main steps. The first step is the electropolymerization of a conducting polymer (pyrrole) onto the pencil graphite electrode (PGE). The second step is the entrapment of silver-doped zinc oxide nanoparticles (nano Ag-ZnO) onto PGE, which has already been doped with polypyrrole (PPy). The third step is the immobilization of the enzyme (xanthine oxidase) onto the modified electrode (nano Ag-ZnO/PPy/PGE) surface. The biosensor was characterized by scanning electron microscopy (SEM). The addition of Ag-doped ZnO nanoparticles into the conducting polymer structure played an important role in the performance of the biosensor by increasing the porous structure of the conducting polymer surface. The electrochemical behaviour of the biosensor was studied by electrochemical impedance spectroscopy (EIS) and chronoamperometry (CA). This enzyme biosensor showed the maximum response at pH 7.40 when +0.7 V was applied to reach 95% of steady-state current at ~3.2 s. The designed biosensor showed high selectivity with a sensitivity of 0.03 µA/mM and a low detection limit of 0.07 µM.


Assuntos
Técnicas Biossensoriais/métodos , Polímeros/química , Pirróis/química , Xantina/análise , Óxido de Zinco/química , Técnicas Eletroquímicas/métodos , Enzimas Imobilizadas/química , Análise de Alimentos/métodos , Limite de Detecção , Nanopartículas/química , Alimentos Marinhos/análise , Prata/química , Xantina Oxidase/química
12.
Eur J Med Chem ; 179: 591-607, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31279293

RESUMO

Antibody-drug conjugates (ADCs) containing pyrrolobenzodiazepine (PBD) dimers are currently being evaluated in human oncology clinical trials with encouraging results. To further improve the therapeutic window, next-generation PBD drug-linker design has focused on the inclusion of additional tumor-selective triggers and use of lower-potency PBDs. ß-Glucuronidase is a well-known target for discovery prodrugs due to increased presence in tumor cells and microenvironment. In this study, a ß-glucuronidase cleavable cap was investigated at the PBD N10-position and compared with corresponding free imine ADCs. SG3600 (glucuronide) ADCs showed in vitro and in vivo efficacy/tolerability comparable to SG3400 (imine) ADCs, and good 50% inhibitory concentration differentials were observed in vitro between control non-antigen-targeted ADCs and targeted ADCs. Dependence on ß-glucuronidase for SG3600 activity was demonstrated through CRISPRCas9 knockdown studies and addition of exogenous ß-glucuronidase. SG3600 showed better serum stability, improved conjugation efficiency and was able to reach high drug-to-antibody ratio without aggregation.


Assuntos
Benzodiazepinas/farmacologia , Dipeptídeos/farmacologia , Glucuronídeos/farmacologia , Imunoconjugados/farmacologia , Pirróis/farmacologia , Benzodiazepinas/síntese química , Benzodiazepinas/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dipeptídeos/química , Relação Dose-Resposta a Droga , Glucuronídeos/química , Humanos , Imunoconjugados/química , Estrutura Molecular , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
13.
Bioelectrochemistry ; 129: 211-217, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31200251

RESUMO

In this paper, we constructed MIL-53 (AlOHbdc, bdc = benzene-1,4-dicarboxylate) /CNTs and Prussian blue (PB) as the double sensitization material of the sensing platform, in which the MIL-53/CNTs hybrid can not only increase the specific surface area but also increase the conductivity of the sensor and PB can play a role in amplifying electrical signals and accelerating electron transmission. Pyrrole was used as monomer and E2 was used as template for electropolymerization to form conductive film. Moreover, the overoxidation/dedoping elution method were used to simplify the experimental process. Under optimal conditions, the MIECS exhibited an excellent sensitivity and high selectivity with a wide linear response range between 10-14 to 10-9 mol L-1 and an estimated detection limit of 6.19 × 10-15 mol L-1.


Assuntos
Técnicas Eletroquímicas , Estradiol/análise , Ferrocianetos/química , Estruturas Metalorgânicas/química , Impressão Molecular , Nanotubos de Carbono/química , Poluentes Químicos da Água/análise , Técnicas Eletroquímicas/métodos , Água Doce/análise , Impressão Molecular/métodos , Polímeros/química , Pirróis/química
14.
Bioelectrochemistry ; 129: 135-143, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31158798

RESUMO

A new and highly selective amperometric biosensor able to analyse choline in clinical samples from patients suffering from renal diseases and receiving repetitive haemodialysis treatment is described. The proposed biosensor is based on choline oxidase immobilized by co-crosslinking onto a novel anti-fouling and anti-interferent membrane. Between the several polymeric films electrosynthesized on a Pt electrode whose permselective behaviours were here investigated, those based on overoxidized polypyrrole/poly(o-aminophenol) bilayer revealed the most effective in rejecting common interferents usually present in biological fluids. The so realized biosensor showed notably analytical performances, displaying linear choline responses up to 100 µM, a sensitivity of 156 nA mM-1 mm-2 and a limit of detection, calculated at a signal-to-noise ratio equal to 3, of 1 µM; further, the within-a-day coefficients of variation for replicate (n = 3) were 2.7% and 1.2% at 100 µM and 10 µM choline levels, respectively. The remarkable performances and anti-interference behaviour allowed us the use of the proposed biosensor for the selective and fouling-free detection of choline in dialysate coming from patients on haemodialysis and even in their unpretreated human sera. Preliminary results gave choline levels in good agreement with the expected values.


Assuntos
Alcaligenes/enzimologia , Oxirredutases do Álcool/química , Técnicas Biossensoriais/métodos , Colina/sangue , Membranas Artificiais , Polímeros/química , Pirróis/química , Colina/análise , Soluções para Diálise/análise , Enzimas Imobilizadas/química , Humanos , Limite de Detecção , Diálise Renal
15.
Anal Chim Acta ; 1074: 80-88, 2019 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-31159942

RESUMO

A rapid and sensitive electrochemical biosensor was constructed to detect Salmonella using invA gene biosensor. The biosensing was based on polyrrole-reduced graphene oxide (PPy-rGO) nanocomposite modified glassy carbon electrode (GCE) and signal amplification with horseradish peroxidase-streptavidin biofunctionalized gold nanoparticles (AuNPs-HRP-SA). PPy-rGO was prepared at 60 °C by chemical reduction of PPy-functionalized graphene oxide (PPy-GO) that was synthesized by in situ polymerization at room temperature. The detection signal was amplified via enzymatic reduction of H2O2 in the presence of hydroquinone (HQ) using AuNPs-HRP-SA as nanotag. Under optimal conditions, the differential pulse voltametric (DPV) signal from the biosensor was linearly related to the logarithm of target invA gene concentrations from 1.0 × 10-16 to 1.0 × 10-10 M, and the limit of detection (LOD) was 4.7 × 10-17 M. The biosensor can also detect Salmonella in the range of 9.6 to 9.6 × 104 CFU mL-1, with LOD of 8.07 CFU mL-1. The biosensor showed good regeneration ability, acceptable selectivity, repeatability and stability, which bode well as an alternative method for Salmonella screening.


Assuntos
Proteínas de Bactérias/genética , Técnicas de Tipagem Bacteriana/métodos , Grafite/química , Nanopartículas Metálicas/química , Polímeros/química , Pirróis/química , Salmonella/isolamento & purificação , Técnicas Biossensoriais/métodos , Carbono , DNA Bacteriano/genética , Técnicas Eletroquímicas/instrumentação , Técnicas Eletroquímicas/métodos , Eletrodos , Enzimas Imobilizadas/química , Ouro/química , Peroxidase do Rábano Silvestre/química , Peróxido de Hidrogênio/química , Hidroquinonas/química , Limite de Detecção , Nanocompostos/química , Hibridização de Ácido Nucleico , Oxirredução , Salmonella/genética , Estreptavidina/química
16.
Adv Mater ; 31(32): e1901677, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31215110

RESUMO

Untethered actuation is important for robotic devices to achieve autonomous motion, which is typically enabled by using batteries. Using enzymes to provide the required electrical charge is particularly interesting as it will enable direct harvesting of fuel components from a surrounding fluid. Here, a soft artificial muscle is presented, which uses the biofuel glucose in the presence of oxygen. Glucose oxidase and laccase enzymes integrated in the actuator catalytically convert glucose and oxygen into electrical power that in turn is converted into movement by the electroactive polymer polypyrrole causing the actuator to bend. The integrated bioelectrode pair shows a maximum open-circuit voltage of 0.70 ± 0.04 V at room temperature and a maximum power density of 0.27 µW cm-2 at 0.50 V, sufficient to drive an external polypyrrole-based trilayer artificial muscle. Next, the enzymes are fully integrated into the artificial muscle, resulting in an autonomously powered actuator that can bend reversibly in both directions driven by glucose and O2 only. This autonomously powered artificial muscle can be of great interest for soft (micro-)robotics and implantable or ingestible medical devices manoeuvring throughout the body, for devices in regenerative medicine, wearables, and environmental monitoring devices operating autonomously in aqueous environments.


Assuntos
Glucose/química , Músculos/química , Oxigênio/química , Polímeros/química , Polivinil/química , Pirróis/química , Aspergillus niger/enzimologia , Fontes de Energia Bioelétrica , Biocombustíveis , Técnicas Biossensoriais , Condutividade Elétrica , Eletricidade , Técnicas Eletroquímicas , Glucose Oxidase/química , Ouro/química , Humanos , Lacase/química , Oxirredução , Estresse Mecânico , Trametes/enzimologia
17.
Molecules ; 24(12)2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-31212790

RESUMO

A solid phase membrane adsorbent-a nylon 6 nanofibers membrane coated by polypyrrole (PPy-PA6-NFsM)-was firstly synthesized and used for extraction of two ß-lactam antibiotics (oxacillin and cloxacillin) in urban river water. Then the analytes were detected by capillary electrophoresis with a diode array detector (CE-DAD). The synthesized nanofibers membrane was characterized by scanning electron microscopy and a Fourier transform infrared spectrometer. The experimental conditions were optimized, including the amount used of PPy-PA6-NFsM, pH of the sample solutions, adsorption volume, and desorption conditions. Under the optimal extraction and separation conditions, the detection limits were found to be 2.0 ng/mL for both oxacillin and cloxacillin. The proposed method was applied to the determination of the two ß-lactams in water samples of an urban river. The recoveries of these two ß-lactams were found to be in the range 84.2-96.4%, demonstrating that PPy-PA6-NFsM has a high extraction capability for these two antibiotics. The relative standard deviations, ranging from 2.26% to 5.29% for intraday measurements and from 2.38% to 7.02% for inter-day determinations, were derived respectively.


Assuntos
Caprolactama/análogos & derivados , Eletroforese Capilar , Nanofibras , Polímeros , Pirróis , Poluentes Químicos da Água , beta-Lactamas , Adsorção , Antibacterianos/análise , Antibacterianos/química , Caprolactama/química , Estrutura Molecular , Nanofibras/química , Nanofibras/ultraestrutura , Polímeros/química , Pirróis/química , Extração em Fase Sólida/métodos , Espectroscopia de Infravermelho com Transformada de Fourier , Poluentes Químicos da Água/análise , Poluentes Químicos da Água/química , beta-Lactamas/química
18.
Drug Discov Today Technol ; 31: 109-123, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31200854

RESUMO

The Ubiquitin/Proteasome System comprises an essential cellular mechanism for regulated protein degradation. Ubiquitination may also promote the assembly of protein complexes that initiate intracellular signaling cascades. Thus, proper regulation of substrate protein ubiquitination is essential for maintaining normal cellular physiology. Deubiquitinases are the class of enzymes responsible for removing ubiquitin modifications from target proteins and have been implicated in regulating human disease. As such, deubiquitinases are now recognized as emerging drug targets. Small molecule deubiquitinase inhibitors have been developed; among those, inhibitors for the deubiquitinases USP7 and USP14 are the best-characterized given that they are structurally validated. In this review we discuss the normal physiological roles of the USP7 and USP14 deubiquitinases as well as the pathological conditions associated with their dysfunction, with a focus on oncology and neurodegenerative diseases. We also review structural biology of USP7 and USP14 enzymes and the characterization of their respective inhibitors, highlighting the various molecular mechanisms by which these deubiquitinases may be functionally inhibited. Finally, we summarize the cellular and in vivo studies performed using the structurally-validated USP7 and USP14 inhibitors.


Assuntos
Pirróis/farmacologia , Ubiquitina Tiolesterase/antagonistas & inibidores , Animais , Humanos , Estrutura Molecular , Pirróis/química , Ubiquitina Tiolesterase/química , Ubiquitina Tiolesterase/metabolismo
19.
J Chromatogr A ; 1603: 23-32, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31230878

RESUMO

The analyses of drugs and metabolites in complex matrices have been widely studied in recent years. However, due to high levels endogenous compounds and matrix complexity, these analyses require a sample pre-treatment step. To this aim, two lab-made extractive phases were integrated to probe electrospray ionization mass spectrometry (PESI-MS) technique for direct analysis of illicit drugs in biological fluids and phorbol esters in Jatropha curcas extract. The polypyrrole (PPy) phase was electropolymerized onto a platinum wire surface by cyclic voltammetry. The molecularly imprinted polymer (MIP) was synthesized and adhered onto a stainless-steel needle with epoxy resin. The PPy-PESI-MS method showed to be linear in a concentration range from 1 to 500 µg L-1, with accuracy values between -2.1 and 14%, and precision values between 0.8 and 10.8%. The MIP-PESI-MS method showed to be linear in a concentration range from 0.9 to 30 mg L-1, with accuracy values between -1.6 and -15.3%, and precision values between 4.1 and 13.5%.


Assuntos
Impressão Molecular/métodos , Preparações Farmacêuticas/análise , Preparações Farmacêuticas/isolamento & purificação , Polímeros/química , Pirróis/química , Microextração em Fase Sólida/métodos , Espectrometria de Massas por Ionização por Electrospray/métodos , Cocaína/análise , Cocaína/isolamento & purificação , Voluntários Saudáveis , Humanos , Jatropha/química , Dietilamida do Ácido Lisérgico/análise , Dietilamida do Ácido Lisérgico/isolamento & purificação , Metanfetamina/análise , Metanfetamina/isolamento & purificação , N-Metil-3,4-Metilenodioxianfetamina/análise , N-Metil-3,4-Metilenodioxianfetamina/isolamento & purificação , Ésteres de Forbol/análise , Ésteres de Forbol/isolamento & purificação , Extratos Vegetais/análise , Extratos Vegetais/isolamento & purificação , Saliva/metabolismo , Aço Inoxidável/química , Urinálise
20.
Eur J Med Chem ; 178: 329-340, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31200235

RESUMO

A novel series of 6-substituted pyrrolo[2,3-d]pyrimidines with reversed amide moieties from the lead compound 1a were designed and synthesized as nonclassical antifolates and as potential antitumor agents. Target compounds 1-9 were successfully obtained through two sequential condensation reactions from the key intermediate 2-amino-6-(2-aminoethyl)-3,7-dihydro-4H-pyrrolo[2,3-d]pyrimidin-4-one. In preliminary antiproliferation assay, all compounds demonstrated submicromolar to nanomolar inhibitory effects against KB tumor cells, whereas compounds 1-3 also exhibited nanomolar antiproliferative activities toward SW620 and A549 cells. In particular, compounds 1-3 were significantly more potent than the positive control methotrexate (MTX) and pemetrexed (PMX) to A549 cells. The growth inhibition induced cell cycle arrest at G1-phase with S-phase suppression. Along with the results of nucleoside protection assays, inhibition assays of dihydrofolate reductase (DHFR) clearly elucidated that the intracellular target of the designed compounds was DHFR. Molecular modeling studies suggested two binding modes of the target compounds with DHFR.


Assuntos
Antineoplásicos/farmacologia , Desenho de Drogas , Antagonistas do Ácido Fólico/farmacologia , Ácido Fólico/metabolismo , Pirimidinas/farmacologia , Pirróis/farmacologia , Tetra-Hidrofolato Desidrogenase/metabolismo , Células A549 , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Antagonistas do Ácido Fólico/síntese química , Antagonistas do Ácido Fólico/química , Humanos , Células KB , Estrutura Molecular , Pirimidinas/síntese química , Pirimidinas/química , Pirróis/síntese química , Pirróis/química , Relação Estrutura-Atividade
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