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1.
AAPS PharmSciTech ; 22(5): 193, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34184163

RESUMO

The human immunodeficiency virus (HIV) impacts up to 37 million people globally, of which 1.8 million are children. To date, there is no cure for HIV, although treatment options such as antiretroviral therapy (ART) are available. ART, which involves a patient taking a combination of antiretrovirals, is being used to treat HIV clinically. Despite the effectiveness of ART, there is currently no palatable pediatric formulation to treat HIV in children, which has hindered patient compliance and overall treatment efficacy. In addition, anti-HIV therapeutics are often poorly water-soluble, and hence have poor bioavailability. In the present study, we developed a pediatric-friendly formulation for anti-HIV therapeutics with improved dissolution characteristics of the therapeutic agents. Lopinavir (LPV) and ritonavir (RTV), available as FDA-approved fixed-dose combination products, were chosen as model ART drugs, and the formulation and processing parameters of spray-dried cyclodextrin (CD)-based LPV and RTV complexes were studied. Results showed that the spray-dried complexes exhibited enhanced dissolution profiles in comparison to pure drugs, particularly spray-dried ß-CD complexes, which showed the most favorable dissolution profiles. This current formulation with enhanced dissolution and taste-masking ability through the use of cyclodextrin has the potential to address the unmet need for the development of suitable pediatric formulations.


Assuntos
Fármacos Anti-HIV/análise , Fármacos Anti-HIV/síntese química , Ciclodextrinas/análise , Ciclodextrinas/síntese química , Desenvolvimento de Medicamentos/métodos , Secagem por Atomização , Fármacos Anti-HIV/uso terapêutico , Criança , Ciclodextrinas/uso terapêutico , Composição de Medicamentos/métodos , Infecções por HIV/tratamento farmacológico , Humanos , Espectroscopia de Ressonância Magnética/métodos , Pediatria/métodos , Difração de Raios X/métodos
2.
Tree Physiol ; 41(3): 416-427, 2021 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-33094330

RESUMO

Our understanding of how conifers respond biochemically to multiple simultaneous herbivore attacks is lacking. Eastern hemlock (Tsuga canadensis; 'hemlock') is fed on by hemlock woolly adelgid (Adelges tsugae; 'adelgid') and by later-instar gypsy moth (Lymantria dispar; 'gypsy moth') caterpillars. The adelgid is a stylet-feeding insect that causes a salicylic acid (SA)-linked response in hemlock, and gypsy moth larvae are folivores that presumably cause a jasmonic acid (JA)-linked response. This system presents an opportunity to study how invasive herbivore-herbivore interactions mediated through host biochemical responses. We used a factorial field experiment to challenge chronically adelgid-infested hemlocks with gypsy moth caterpillars. We quantified 17 phytohormones, 26 phenolic and terpene metabolites, and proanthocyanidin, cell wall-bound (CW-bound) phenolic, and lignin contents. Foliage infested with adelgid only accumulated gibberellins and SA; foliage challenged by gypsy moth only accumulated JA phytohormones. Gypsy moth folivory on adelgid-infested foliage reduced the accumulation of JA phytohormones and increased the SA levels. Both herbivores increased CW-bound phenolics and gypsy moth increased lignin content when feeding alone but not when feeding on adelgid-infested foliage. Our study illustrates the importance of understanding the biochemical mechanisms and signaling antagonism underlying tree responses to multiple stresses and of disentangling local and systemic stress signaling in trees.


Assuntos
Hemípteros , Traqueófitas , Animais , Herbivoria , Árvores , Tsuga
3.
Molecules ; 25(23)2020 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-33261035

RESUMO

Cyclodextrins (CDs) are naturally occurring cyclic oligosaccharides consisting of multiple glucose subunits. CDs are widely used in host-guest chemistry and biochemistry due to their structural advantages, biocompatibility, and ability to form inclusion complexes. Recently, CDs have become of high interest in the field of medical imaging as a potential scaffold for the development of a large variety of the contrast agents suitable for magnetic resonance imaging, ultrasound imaging, photoacoustic imaging, positron emission tomography, single photon emission computed tomography, and computed tomography. The aim of this review is to summarize and highlight the achievements in the field of cyclodextrin-based contrast agents for medical imaging.


Assuntos
Meios de Contraste/química , Ciclodextrinas/química , Diagnóstico por Imagem/métodos , Animais , Humanos
4.
ACS Chem Neurosci ; 11(24): 4478-4488, 2020 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-33284578

RESUMO

To combat the bottlenecks in drug discovery and development, a pipeline to identify neuropharmacological candidates using in silico, in vitro, and receptor specific assays was devised. The focus of this pipeline was to identify metabolites with the ability to reduce neuroinflammation, due to the implications that chronic neuroinflammation has in chronic pain and neurodegenerative diseases. A library of pure compounds isolated from the cyanobacterium Trichodesmium thiebautii was evaluated using this method. In silico analysis of drug likelihood and in vitro permeability analysis using the parallel artificial membrane permeability assay (PAMPA) highlighted multiple metabolites of interest from the library. Murine BV-2 microglia were used in conjunction with the Griess assay to determine if metabolites could reduce lipopolysaccharide induced neuroinflammation followed by analysis of pro-inflammatory cytokine concentrations in the supernatant of the treated cell cultures. The nontoxic metabolite unnarmicin D was further evaluated due to its moderate permeability in the PAMPA assay, promising ADME data, modulation of all cytokines tested, and prediction as an opioid receptor ligand. Molecular modeling of unnarmicin D to the µ and δ opioid receptors showed strong theoretical binding potential to the µ opioid receptor. In vitro binding assays validated this pipeline showing low micromolar binding affinity for the µ opioid receptor launching the potential for further analysis of unnarmicin D derivatives for the treatment of pain and neuroinflammation related diseases.


Assuntos
Analgésicos Opioides , Receptores Opioides delta , Animais , Anti-Inflamatórios , Camundongos , Peptídeos Cíclicos , Receptores Opioides mu , Trichodesmium
5.
ACS Omega ; 5(43): 27783-27788, 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33163761

RESUMO

A decacationic water-soluble pillar[5]arene possessing a nonsolvated hydrophobic core has been designed and synthesized. This supramolecular host is capable of binding xenon, as evidenced by hyperCEST depletion experiments. Fluorescence-based studies also demonstrate that xenon binds into the cavity of the pillararene with an association constant of 4.6 × 103 M-1. These data indicate that the water-soluble pillararene is a potential scaffold for building contrast agents that can be detected by xenon-129 magnetic resonance imaging.

6.
ACS Omega ; 4(3): 6077-6083, 2019 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-31459755

RESUMO

A mild, one-pot procedure to produce 3-substituted allylic alcohols from α,ß-unsaturated ketones is described. The addition of an organolithium nucleophile produces a tertiary allylic alcohol as an intermediate, which undergoes a 1,3-OH-migration assisted by FeCl2. The proposed mechanism indicates that a syn-facial migration occurs for the major product. Yields as high as 98% for the one-pot reaction are reported.

7.
ACS Omega ; 3(1): 677-681, 2018 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31457922

RESUMO

Hyperpolarized (HP) xenon-129 (Xe) magnetic resonance (MR) imaging has the potential to detect biological analytes with high sensitivity and high resolution when coupled with xenon-encapsulating molecular probes. Despite the development of numerous HP Xe probes, one of the challenges that has hampered the translation of these agents from in vitro demonstration to in vivo testing is the difficulty in synthesizing the Xe-encapsulating cage molecule. In this study, we demonstrate that a pseudorotaxane, based on a γ-cyclodextrin macrocycle, is easily synthesized in one step and is detectable using HyperCEST-enhanced 129Xe MR spectroscopy.

8.
Sci Rep ; 7: 41027, 2017 01 20.
Artigo em Inglês | MEDLINE | ID: mdl-28106110

RESUMO

The Hyperpolarized gas Chemical Exchange Saturation Transfer (HyperCEST) Magnetic Resonance (MR) technique has the potential to increase the sensitivity of a hyperpolarized xenon-129 MRI contrast agent. Signal enhancement is accomplished by selectively depolarizing the xenon within a cage molecule which, upon exchange, reduces the signal in the dissolved phase pool. Herein we demonstrate the in vivo detection of the cucurbit[6]uril (CB6) contrast agent within the vasculature of a living rat. Our work may be used as a stepping stone towards using the HyperCEST technique as a molecular imaging modality.


Assuntos
Vasos Sanguíneos/diagnóstico por imagem , Hidrocarbonetos Aromáticos com Pontes/análise , Meios de Contraste/análise , Imidazóis/análise , Imageamento por Ressonância Magnética/métodos , Isótopos de Xenônio/análise , Animais , Ratos
9.
Contrast Media Mol Imaging ; 11(4): 285-90, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27071809

RESUMO

Xenon based biosensors have the potential to detect and localize biomarkers associated with a wide variety of diseases. The development and nuclear magnetic resonance (NMR) characterization of cage molecules which encapsulate hyperpolarized xenon is imperative for the development of these xenon biosensors. We acquired (129) Xe NMR spectra, and magnetic resonance images and a HyperCEST saturation map of cucurbit[6]uril (CB6) in whole bovine blood. We observed a mean HyperCEST depletion of 84% (n = 5) at a concentration of 5 mM and 74% at 2.5 mM. Additionally, we collected these data using a pulsed HyperCEST saturation pre-pulse train with a SAR of 0.025 W/kg which will minimize any potential RF heating in animal or human tissue. Copyright © 2016 John Wiley & Sons, Ltd.


Assuntos
Técnicas Biossensoriais/métodos , Hidrocarbonetos Aromáticos com Pontes/sangue , Imidazóis/sangue , Imageamento por Ressonância Magnética/métodos , Xenônio/química , Animais , Bovinos , Eritrócitos/química , Humanos , Espectroscopia de Ressonância Magnética/métodos
10.
Tetrahedron Lett ; 56(41): 5610-5612, 2015 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-26478603

RESUMO

The formation of carbon-nitrogen (C-N) bonds via an umpolung substitution reaction has been achieved at -78 °C without the need for catalysts, ligands, or additives. The scope is limited to aryl Grignard reagents with N-chloroamines. The findings in this manuscript serve as a reference point for all C-N bond formation involving N-chloroamines and organometallic reagents. Knowing the yields of uncatalyzed reactions will be useful when determining the success of future catalytic methods.

11.
Org Lett ; 17(21): 5208-11, 2015 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-26479446

RESUMO

The vanadium-catalyzed oxidative coupling of substituted 2-arylimidiazo[1,2-a]pyridines to N-methylmorpholine oxide, which acts as both a coupling partner and an oxidant, has been achieved. This reaction was applied to various substituted imidiazo[1,2-a]pyridine and indole substrates, resulting in yields as high as 90%. Mechanistic investigations indicate that the reaction may proceed via a Mannich-type process. This work demonstrates how oxidative aminomethylation can be used as a useful method to introduce tertiary amines into heterocycles, thus providing an alternative method for conventional Mannich-type reactions.


Assuntos
Compostos Heterocíclicos com 3 Anéis/química , Compostos Heterocíclicos de 4 ou mais Anéis/síntese química , Imidazóis/química , Morfolinas/química , Piridinas/química , Vanádio/química , Catálise , Compostos Heterocíclicos de 4 ou mais Anéis/química , Estrutura Molecular , Oxidantes/química , Oxirredução , Acoplamento Oxidativo
12.
Chem Commun (Camb) ; 51(17): 3574-7, 2015 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-25632832

RESUMO

A new approach for the direct amination of 2-phenylpyridine derivatives using a diphthalimide-iodane and copper triflate has been developed. A series of different 2-phenylpyridine derivatives were aminated with yields up to 88%. Mechanistic investigations indicate that the reaction proceeds via a copper-mediated single electron transfer.


Assuntos
Aminas/síntese química , Piridinas/química , Aminação , Aminas/química , Estrutura Molecular , Estereoisomerismo
13.
Org Biomol Chem ; 13(9): 2537-40, 2015 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-25592739

RESUMO

The development of a ß-CCT-lanthanide conjugate that binds the dopamine transporter (DAT) with high affinity (K(d) = 303 nM) is described. Contrast agents such as the one described herein could be used as molecular probes to directly study the binding of small molecules to receptors such as DAT via MRI, PET or SPECT.


Assuntos
Carbolinas/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/química , Elementos da Série dos Lantanídeos/química , Compostos Organometálicos/química , Sítios de Ligação , Células HEK293 , Humanos , Estrutura Molecular , Compostos Organometálicos/síntese química
14.
Org Lett ; 17(2): 358-61, 2015 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-25539392

RESUMO

A novel protocol for the regioselective intermolecular amination of various arenes has been developed. By using an I(III) oxidant in the presence of a Au(I) catalyst, a direct and novel route for regioselectively accessing a variety of substituted aniline moieties has been achieved with yields as high as 90%. Mechanistic insight suggests that regioselectivity can be predicted based on electrophilic aromatic metalation patterns.


Assuntos
Compostos de Anilina/química , Compostos de Anilina/síntese química , Ouro/química , Compostos Organometálicos/química , Aminação , Catálise , Estrutura Molecular , Oxirredução , Estereoisomerismo
15.
Tetrahedron Lett ; 55(10): 1729-1732, 2014 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-24764603

RESUMO

Electron poor benzimidazole substrates were arylated via an intramolecular cross-dehydrogenative coupling (CDC) reaction. These CDC reactions were catalyzed by a Pd(II)/Cu(I) catalyst system, capable of producing moderate yields on a large library of substrates. The substrate scope consisted of tethered arene-benzimidazoles that upon coupling, produced a fused polycyclic motif.

16.
Org Lett ; 16(3): 868-71, 2014 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-24450989

RESUMO

The iron-catalyzed arylation of aromatic heterocycles, such as pyridines, thiophenes, and furans, has been achieved. The use of an imine directing group allowed for the ortho functionalization of these heterocycles with complete conversion in 15 min at 0 °C. Yields up to 88% were observed in the synthesis of 15 heterocyclic biaryls.


Assuntos
Furanos/síntese química , Compostos Heterocíclicos/química , Compostos Heterocíclicos/síntese química , Ferro/química , Piridinas/síntese química , Tiofenos/síntese química , Catálise , Ligação de Hidrogênio , Estrutura Molecular
17.
Tetrahedron ; 69(22): 4429-4435, 2013 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-23729868

RESUMO

The effects of oxidant and organic acid additives on the oxidative cross-coupling reactions of electron rich heterocycles such as benzofuran with benzene were studied. Both regioselectivity and reaction rate could be controlled by varying the condition parameters. Furthermore, mechanistic insight was achieved via kinetic studies which indicate that reactions that are oxidized by the heteropoly acid H4PMo11VO40 operate via a Pd(II)/Pd(IV) mechanisms, while reactions oxidized by either AgOAc or Cu(OAc)2 operate by a Pd(II)/Pd(0) mechanism.

18.
J Chem Educ ; 90(3): 376-378, 2013 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-23504657

RESUMO

A modern apparatus for performing flash chromatography using commercially available, prepacked silica cartridges has been developed. The key advantage of this system, when compared to traditional flash chromatography, is its use of commercially available silica cartridges, which obviates the need for students to handle silica gel. The apparatus has been tested for its ability to perform separations that are commonly found in organic chemistry teaching laboratories, and a laboratory module that combines the techniques of thin-layer chromatography, gas chromatography, and flash chromatography is described. The performance of this new chromatography apparatus was comparable to a traditional flash chromatography column.

19.
J Am Chem Soc ; 133(49): 19960-5, 2011 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-22010982

RESUMO

The development of a novel intermolecular oxidative amination reaction, a synthetic transformation that involves the simultaneous functionalization of both a N-H and C-H bond, is described. The process, which is mediated by an I(III) oxidant and contains no metal catalysts, provides a rapid and green method for synthesizing protected anilines from simple arenes and phthalimide. Mechanistic investigations indicate that the reaction proceeds via nucleophilic attack of the phthalimide on an aromatic radical cation, as opposed to the electrophilic aromatic amination that has been reported for other I(III) amination reactions. The application of this new reaction to the synthesis of a variety of substituted aniline derivatives is demonstrated.


Assuntos
Compostos de Anilina/síntese química , Química Verde/métodos , Aminação , Compostos de Anilina/química , Catálise , Química Verde/economia , Oxirredução , Ftalimidas/síntese química , Ftalimidas/química
20.
Chem Commun (Camb) ; 47(16): 4679-81, 2011 Apr 28.
Artigo em Inglês | MEDLINE | ID: mdl-21423956

RESUMO

A new and efficient scheme for the synthesis of one of the best known inhibitors of botulinum neurotoxin serotype A (BoNTA) is reported herein. The synthetic route involves two palladium-catalyzed C-H functionalization reactions, formally activating three C-H bonds.


Assuntos
Toxinas Botulínicas Tipo A/antagonistas & inibidores , Tiofenos/farmacologia , Catálise , Estrutura Molecular , Compostos Organometálicos/química , Paládio/química , Estereoisomerismo , Relação Estrutura-Atividade , Tiofenos/síntese química , Tiofenos/química
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