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[PMID]:29279438
[Au] Autor:Ebitani M; Ebitani T
[Ad] Endereço:Faculty of Pharmaceutical Sciences, Toyama Medical and Pharmaceutical University.
[Ti] Título:[Rotational Isomers of Diphenhydramine].
[So] Source:Yakugaku Zasshi;138(3):417-424, 2018 Mar 01.
[Is] ISSN:1347-5231
[Cp] País de publicação:Japan
[La] Idioma:jpn
[Ab] Resumo: Diphenhydramine (DP), an antihistaminic agent, may become colored and daker or more fluorescent during storage. Herein, we spectroscopically examined the causes of this phenomenon under various DP storage conditions and durations. The infrared vibration-rotation spectrum shows multiple Gauche (G)-type conformers with different intramolecular n→π interaction strengths. The splitting pattern of the dimethylamino group protons in the H-NMR spectrum indicates that DP is mainly in the G-type with a small portion in the Trans (T)-type. The correlation between the red-shifted peak intensity in the UV•VIS absorbance spectrum and the coloring progression indicates a decreased intramolecular n→π interaction of the G-type under elevated temperature during storage. Enhanced fluorescence detected in the Excitation•Fluorescence spectrum demonstrates G-type (quenching) to T-type (fluorescent) conformation conversion, which is due to activated internal rotation of the dimethylamino group under elevated storage temperature and electronic excitation in the phenyl groups under light irradiation during storage. A signal detected in the ESR spectrum corresponds to the G-type charge transfer (CT) structure wherein part of the nonbonding electron pair on the N atom is intramolecularly redistributed to the phenyl groups. The CT structure presents the G-type quenching characteristics, whereas weak CT bonding corresponds to coloring. The results indicate that the quenching G-type is converted to T-type by heat or light to become color faded and bright with enhanced fluorescence and that T-type is reverted to G-type after storage under cool and dark conditions or by vacuum distillation to lose fluorescence.
[Mh] Termos MeSH primário: Difenidramina/química
Estabilidade de Medicamentos
Armazenamento de Medicamentos
Antagonistas dos Receptores Histamínicos/química
[Mh] Termos MeSH secundário: Cor
Espectroscopia de Ressonância de Spin Eletrônica
Fluorescência
Isomerismo
Luz
Espectroscopia de Ressonância Magnética
Conformação Molecular
Rotação
Espectrometria de Fluorescência
Espectrofotometria Infravermelho
Análise Espectral
Temperatura Ambiente
Vibração
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Histamine Antagonists); 8GTS82S83M (Diphenhydramine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171228
[St] Status:MEDLINE
[do] DOI:10.1248/yakushi.17-00175


  2 / 64414 MEDLINE  
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[PMID]:28470986
[Au] Autor:Wang L; Wang Y; Chai Y; Kang Y; Sun C; Zeng S
[Ad] Endereço:Institute of Drug Metabolism and Pharmaceutical Analysis, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China.
[Ti] Título:Nickel(II)-assisted enantiomeric differentiation and quantitation of tadalafil by direct electrospray ionization mass spectrometry.
[So] Source:J Mass Spectrom;52(7):411-416, 2017 Jul.
[Is] ISSN:1096-9888
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A facile method based on electrospray mass spectrometry was established and validated for the differentiation of enantiomeric tadalafil isomers without using chiral chromatographic separation. The enantiomers were coupled with a chiral selector to form diastereomeric complex ions. Nickel-tadalafil complexes, [Ni (tadalafil)(l-Trp)-H] , produced a characteristic fragment ion at m/z 524 by loss of 1-methyl-1,6-dihydropyrazine-2,5-dione via collision-induced dissociation. The relative abundance of this fragment ion to the precursor contributed to differentiate tadalafil enantiomers, and energy-resolved product-ion spectra were applied to determine the molar composition of tadalafil in the mixture (R,R and S,S) as well. In addition, the other two forms of stereomeric isomers of tadalafil (R,S and S,R) could be also distinguished and analyzed by this method. The method was validated in different types of mass spectrometers (AB quadrupole time-of-flight and Bruker ion trap) and also verified by a chiral high-performance liquid chromatography coupled with quadrupole time-of-flight. The chiral determination of tadalafil using MS method proved to be rapid (1-min run time for each sample) and to have the same accuracy and precision comparable to chiral liquid chromatography mass spectrometry methods. This method provides an alternative to commonly used chromatographic technique for chiral determination and is particularly useful in rapid screening in enantioselective synthesis and enantiomeric impurity detection in pharmaceutical industry. Copyright © 2017 John Wiley & Sons, Ltd.
[Mh] Termos MeSH primário: Complexos de Coordenação/análise
Níquel/química
Inibidores da Fosfodiesterase 5/análise
Tadalafila/análise
[Mh] Termos MeSH secundário: Cromatografia Líquida de Alta Pressão/métodos
Complexos de Coordenação/química
Contaminação de Medicamentos
Conformação Molecular
Inibidores da Fosfodiesterase 5/química
Espectrometria de Massas por Ionização por Electrospray/métodos
Estereoisomerismo
Tadalafila/química
[Pt] Tipo de publicação:JOURNAL ARTICLE; VALIDATION STUDIES
[Nm] Nome de substância:
0 (Coordination Complexes); 0 (Phosphodiesterase 5 Inhibitors); 742SXX0ICT (Tadalafil); 7OV03QG267 (Nickel)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180309
[Lr] Data última revisão:
180309
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170505
[St] Status:MEDLINE
[do] DOI:10.1002/jms.3939


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[PMID]:29339721
[Au] Autor:Kilic S; Felekyan S; Doroshenko O; Boichenko I; Dimura M; Vardanyan H; Bryan LC; Arya G; Seidel CAM; Fierz B
[Ad] Endereço:Laboratory of Biophysical Chemistry of Macromolecules, Institute of Chemical Sciences and Engineering (ISIC), Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland.
[Ti] Título:Single-molecule FRET reveals multiscale chromatin dynamics modulated by HP1α.
[So] Source:Nat Commun;9(1):235, 2018 01 16.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The dynamic architecture of chromatin fibers, a key determinant of genome regulation, is poorly understood. Here, we employ multimodal single-molecule Förster resonance energy transfer studies to reveal structural states and their interconversion kinetics in chromatin fibers. We show that nucleosomes engage in short-lived (micro- to milliseconds) stacking interactions with one of their neighbors. This results in discrete tetranucleosome units with distinct interaction registers that interconvert within hundreds of milliseconds. Additionally, we find that dynamic chromatin architecture is modulated by the multivalent architectural protein heterochromatin protein 1α (HP1α), which engages methylated histone tails and thereby transiently stabilizes stacked nucleosomes. This compacted state nevertheless remains dynamic, exhibiting fluctuations on the timescale of HP1α residence times. Overall, this study reveals that exposure of internal DNA sites and nucleosome surfaces in chromatin fibers is governed by an intrinsic dynamic hierarchy from micro- to milliseconds, allowing the gene regulation machinery to access compact chromatin.
[Mh] Termos MeSH primário: Cromatina/metabolismo
Proteínas Cromossômicas não Histona/metabolismo
Transferência Ressonante de Energia de Fluorescência/métodos
Nucleossomos/metabolismo
[Mh] Termos MeSH secundário: Animais
Cromatina/química
Cromatina/genética
DNA/química
DNA/genética
DNA/metabolismo
Regulação da Expressão Gênica
Histonas/metabolismo
Cinética
Metilação
Microscopia de Fluorescência
Conformação Molecular
Conformação de Ácido Nucleico
Nucleossomos/química
Nucleossomos/genética
Ligação Proteica
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Chromatin); 0 (Chromosomal Proteins, Non-Histone); 0 (Histones); 0 (Nucleosomes); 107283-02-3 (heterochromatin-specific nonhistone chromosomal protein HP-1); 9007-49-2 (DNA)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180118
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02619-5


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[PMID]:29335413
[Au] Autor:Abberley JP; Killah R; Walker R; Storey JMD; Imrie CT; Salamonczyk M; Zhu C; Gorecka E; Pociecha D
[Ad] Endereço:Department of Chemistry, King's College, University of Aberdeen, Aberdeen, AB24 3UE, UK.
[Ti] Título:Heliconical smectic phases formed by achiral molecules.
[So] Source:Nat Commun;9(1):228, 2018 01 15.
[Is] ISSN:2041-1723
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Chiral symmetry breaking in soft matter is a hot topic of current research. Recently, such a phenomenon was found in a fluidic phase showing orientational order of molecules-the nematic phase; although built of achiral molecules, the phase can exhibit structural chirality-average molecular direction follows a short-pitch helix. Here, we report a series of achiral asymmetric dimers with an odd number of atoms in the spacer, which form twisted structures in nematic as well as in lamellar phases. The tight pitch heliconical nematic (N ) phase and heliconical tilted smectic C (SmC ) phase are formed. The formation of a variety of helical structures is accompanied by a gradual freezing of molecular rotation. In the lowest temperature smectic phase, HexI, the twist is expressed through the formation of hierarchical structure: nanoscale helices and mesoscopic helical filaments. The short-pitch helical structure in the smectic phases is confirmed by resonant X-ray measurements.
[Mh] Termos MeSH primário: Cristais Líquidos/química
Conformação Molecular
Nanoestruturas/química
Transição de Fase
[Mh] Termos MeSH secundário: Dicroísmo Circular
Isomerismo
Microscopia de Força Atômica
Modelos Químicos
Modelos Moleculares
Estrutura Molecular
Difração de Raios X
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T; RESEARCH SUPPORT, U.S. GOV'T, NON-P.H.S.
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180305
[Lr] Data última revisão:
180305
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180117
[St] Status:MEDLINE
[do] DOI:10.1038/s41467-017-02626-6


  5 / 64414 MEDLINE  
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[PMID]:29386433
[Au] Autor:Hatakeyama S
[Ad] Endereço:Graduate School of Biomedical Sciences, Nagasaki University.
[Ti] Título:[Stereocontrolled Total Synthesis of Biologically Active Natural Products].
[So] Source:Yakugaku Zasshi;138(2):191-209, 2018.
[Is] ISSN:1347-5231
[Cp] País de publicação:Japan
[La] Idioma:jpn
[Ab] Resumo: This review article describes the total syntheses of englerin A, ophiodilactones A and B, marinomycin A, N-methylwelwitindolinone C isothiocyanate, tirandamycins A-D, and tirandalydigin, which possess intriguing biological activities and challenging structures with characteristic ring systems. The focus is on the synthetic methodologies that lead to the highly stereocontrolled assembly of these natural products.
[Mh] Termos MeSH primário: Produtos Biológicos/síntese química
[Mh] Termos MeSH secundário: Alcenos/síntese química
Alcenos/química
Aminoglicosídeos/síntese química
Aminoglicosídeos/química
Derivados de Benzeno/síntese química
Derivados de Benzeno/química
Produtos Biológicos/química
Alcaloides de Indol/síntese química
Alcaloides de Indol/química
Lactonas/síntese química
Lactonas/química
Macrolídeos/síntese química
Macrolídeos/química
Conformação Molecular
Sesquiterpenos de Guaiano/síntese química
Sesquiterpenos de Guaiano/química
Estereoisomerismo
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Alkenes); 0 (Aminoglycosides); 0 (Benzene Derivatives); 0 (Biological Products); 0 (Indole Alkaloids); 0 (Lactones); 0 (Macrolides); 0 (N-methylwelwitindolinone B isothiocyanate); 0 (Sesquiterpenes, Guaiane); 0 (englerin A); 0 (marinomycin A); 0 (ophiodilactone A); 0 (ophiodilactone B); 0 (tirandamycin C); 0 (tirandamycin D); 114118-91-1 (tirandalydigin); 34429-70-4 (tirandamycin A); 60587-14-6 (tirandamycin B)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180228
[Lr] Data última revisão:
180228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180202
[St] Status:MEDLINE
[do] DOI:10.1248/yakushi.17-00187


  6 / 64414 MEDLINE  
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[PMID]:29172467
[Au] Autor:Casini A; Woods B; Wenzel M
[Ad] Endereço:School of Chemistry, Cardiff University , Main Building, Park Place, CF10 3AT Cardiff, United Kingdom.
[Ti] Título:The Promise of Self-Assembled 3D Supramolecular Coordination Complexes for Biomedical Applications.
[So] Source:Inorg Chem;56(24):14715-14729, 2017 Dec 18.
[Is] ISSN:1520-510X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:In the supramolecular chemistry field, coordination-driven self-assembly has provided the basis for tremendous growth across many subdisciplines, spanning from fundamental investigations regarding the design and synthesis of new architectures to defining different practical applications. Within this framework, supramolecular coordination complexes (SCCs), defined as large chemical entities formed from smaller precursor building blocks of ionic metal nodes and organic multidentate ligands, resulting in intricate and well-defined supramolecular structures, hold great promise. Notably, interest in the construction of discrete 3D molecular architectures, such as those offered by SCCs, has experienced extraordinary progress because of their potential application as sensors, catalysts, probes, and containers and in basic host-guest chemistry. Despite numerous synthetic efforts and a number of inherent favorable properties, the field of 3D SCCs for biomedical applications is still in its infancy. This Viewpoint focuses on 3D SCCs, specifically metallacages and helicates, first briefly presenting the fundamentals in terms of the synthesis and characterization of their host-guest properties, followed by an overview of the possible biological applications with representative examples. Thus, emphasis will be given in particular to metallacages as drug delivery systems and to chiral helicates as DNA recognition domains. Overall, we will provide an update on the state-of-the-art literature and will define the challenges in this fascinating research area at the interface of different disciplines.
[Mh] Termos MeSH primário: Complexos de Coordenação/química
Portadores de Fármacos/química
Metais/química
[Mh] Termos MeSH secundário: Animais
DNA/análise
Sistemas de Liberação de Medicamentos/métodos
Corantes Fluorescentes/química
Seres Humanos
Substâncias Intercalantes/química
Ligantes
Modelos Moleculares
Conformação Molecular
Conformação de Ácido Nucleico
RNA/análise
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Coordination Complexes); 0 (Drug Carriers); 0 (Fluorescent Dyes); 0 (Intercalating Agents); 0 (Ligands); 0 (Metals); 63231-63-0 (RNA); 9007-49-2 (DNA)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180228
[Lr] Data última revisão:
180228
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171128
[St] Status:MEDLINE
[do] DOI:10.1021/acs.inorgchem.7b02599


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[PMID]:29345270
[Au] Autor:Chawla M; Autiero I; Oliva R; Cavallo L
[Ad] Endereço:King Abdullah University of Science and Technology (KAUST), Physical Sciences and Engineering Division, Kaust Catalysis Center, Thuwal 23955-6900, Saudi Arabia. mohitchawla.bt@gmail.com luigi.cavallo@kaust.edu.sa.
[Ti] Título:Energetics and dynamics of the non-natural fluorescent 4AP:DAP base pair.
[So] Source:Phys Chem Chem Phys;20(5):3699-3709, 2018 Jan 31.
[Is] ISSN:1463-9084
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:The fluorescent non-natural 4-aminophthalimide (4AP) base, when paired to the complementary 2,4-diaminopyrimidine (DAP) nucleobase, is accommodated in a B-DNA duplex being efficiently recognized and incorporated by DNA polymerases. To complement the experimental studies and rationalize the impact of the above non-natural bases on the structure, stability and dynamics of nucleic acid structures, we performed quantum mechanics (QM) calculations along with classical molecular dynamics (MD) simulations. QM calculations were initially focused on the geometry and energetics of the 4AP:DAP non-natural pair and of H-bonded base pairs between 4AP and all the natural bases in their classical Watson-Crick geometries. The QM calculations indicate that the 4AP:DAP pair, despite the fact that it can form 3 H-bonds in a classic Watson-Crick geometry, has a stability comparable to the A:T pair. Then, we extended the study to reverse Watson-Crick geometries, characteristic of parallel strands. MD simulations were carried out on two 13-mer DNA duplexes, featuring a central 4AP:DAP or A:T pair, respectively. No major structural deformation of the duplex was observed during the MD simulation. Snapshots from the MD simulations were subjected to QM calculations to investigate the 4AP:DAP interaction energy when embedded into a duplex structure, and to investigate the impact of the two non-natural bases on the stacking interactions with adjacent bases in the DNA duplex. We found a slight increase in stacking interactions involving the 4AP:DAP pair, counterbalanced by a moderate decrease in H-bonding interactions of the 4AP:DAP and of the adjacent base pairs in the duplex. The results of our study are in agreement with experimental data and complement them by providing an insight into which factors contribute positively and which factors contribute negatively to the structural compatibility of the fluorescent 4AP:DAP pair with a B-DNA structure.
[Mh] Termos MeSH primário: Ftalimidas/química
Pirimidinas/química
[Mh] Termos MeSH secundário: Pareamento de Bases
DNA de Forma B/química
Ligações de Hidrogênio
Conformação Molecular
Simulação de Dinâmica Molecular
Ftalimidas/metabolismo
Pirimidinas/metabolismo
Teoria Quântica
Termodinâmica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (4-aminophthalimide); 0 (DNA, B-Form); 0 (Phthalimides); 0 (Pyrimidines); 156-81-0 (2,4-diaminopyrimidine)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180119
[St] Status:MEDLINE
[do] DOI:10.1039/c7cp07400j


  8 / 64414 MEDLINE  
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[PMID]:29327000
[Au] Autor:Nikolaienko TY; Bulavin LA
[Ad] Endereço:Taras Shevchenko National University of Kyiv, Faculty of Physics, 64/13, Volodymyrska Street, City of Kyiv, 01601, Ukraine. tim_mail@ukr.net.
[Ti] Título:Atomic charges for conformationally rich molecules obtained through a modified principal component regression.
[So] Source:Phys Chem Chem Phys;20(4):2890-2903, 2018 Jan 24.
[Is] ISSN:1463-9084
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:A modification of the principal component regression model is proposed for obtaining a fixed set of atomic charges (referred to as dipole-derived charges) optimized for reproducing the dipole moment of a conformationally rich molecule, i.e., a molecule with multiple local minima on the potential energy surface. The method does not require any adjustable parameters and requires the geometries of conformers, their dipole moments and atomic polar tensor (APT) charges as the only input data. The fixed atomic charges generated by the method not only reproduce the molecular dipole moment in all the conformers accurately, but are also numerically close to the APT charges, thereby ensuring accurate reproduction of the dipole moment variations caused by small geometrical distortions (e.g., by vibrations) of the conformers. The proposed method has been applied to canonical 2'-deoxyribonucleotides, the model DNA monomers, and the dipole-derived charges have been shown to outperform both the averaged APT and RESP charges in reproducing the dipole moments of large sets of conformers, thus demonstrating a potential usefulness of the dipole-derived charges as a 'reference point' for modeling polarization effects in conformationally rich molecules.
[Mh] Termos MeSH primário: Desoxirribonucleotídeos/química
[Mh] Termos MeSH secundário: Modelos Moleculares
Conformação Molecular
Teoria Quântica
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Deoxyribonucleotides)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180113
[St] Status:MEDLINE
[do] DOI:10.1039/c7cp05703b


  9 / 64414 MEDLINE  
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[PMID]:28741644
[Au] Autor:Bieszczad B; Gilheany DG
[Ad] Endereço:Centre for Synthesis and Chemical Biology, School of Chemistry, University College Dublin, Belfield, Dublin 4, Ireland. declan.gilheany@ucd.ie.
[Ti] Título:Highly stereoselective construction of the C2 stereocentre of α-tocopherol (vitamin E) by asymmetric addition of Grignard reagents to ketones.
[So] Source:Org Biomol Chem;15(31):6483-6492, 2017 Aug 09.
[Is] ISSN:1477-0539
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Tertiary alcohol precursors of both C2 diastereoisomers of α-tocopherol were prepared in three ways by our recently reported asymmetric Grignard synthesis. The versatility of Grignard chemistry inherent in its three-way disconnection was exploited to allow the synthesis of three product grades: 77 : 23 dr (5 steps), 81 : 19 dr (5 steps) and 96 : 4 dr (7 steps, one gram scale) from readily available and abundant starting materials. The products were converted to their respective α-tocopherols in 3 steps, which allowed a definitive re-assignment of their absolute configurations.
[Mh] Termos MeSH primário: Cetonas/química
Vitaminas/síntese química
alfa-Tocoferol/síntese química
[Mh] Termos MeSH secundário: Álcoois/síntese química
Álcoois/química
Técnicas de Química Sintética
Indicadores e Reagentes
Cetonas/síntese química
Conformação Molecular
Estereoisomerismo
Vitaminas/química
alfa-Tocoferol/química
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Alcohols); 0 (Indicators and Reagents); 0 (Ketones); 0 (Vitamins); H4N855PNZ1 (alpha-Tocopherol)
[Em] Mês de entrada:1802
[Cu] Atualização por classe:180226
[Lr] Data última revisão:
180226
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170726
[St] Status:MEDLINE
[do] DOI:10.1039/c7ob00751e


  10 / 64414 MEDLINE  
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[PMID]:28463561
[Au] Autor:Tian S; Wang X; Li L; Zhang X; Li Y; Zhu F; Hou T; Zhen X
[Ad] Endereço:Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University , Suzhou, Jiangsu 215123, China.
[Ti] Título:Discovery of Novel and Selective Adenosine A Receptor Antagonists for Treating Parkinson's Disease through Comparative Structure-Based Virtual Screening.
[So] Source:J Chem Inf Model;57(6):1474-1487, 2017 06 26.
[Is] ISSN:1549-960X
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Among non-dopaminergic strategies for combating Parkinson's disease (PD), antagonism of the A adenosine receptor (AR) has emerged to show great potential. In this study, on the basis of two crystal structures of the A AR with the best capability to distinguish known antagonists from decoys, docking-based virtual screening (VS) was conducted to identify novel A AR antagonists. A total of 63 structurally diverse compounds identified by VS were submitted to experimental testing, and 11 of them exhibited substantial activity against the A AR (K < 10 µM), including two compounds with K below 1 µM (compound 43, 0.42 µM; compound 51, 0.27 µM) and good A /A selectivity (fold < 0.1). Compounds 43 and 51 demonstrated antagonistic activity according to the results of cAMP measurements (cAMP IC = 1.67 and 1.80 µM, respectively) and showed good efficacy in the haloperidol-induced catalepsy (HIC) rat model for PD at doses of up to 30 mg/kg. Further lead optimization based on a substructure searching strategy led to the discovery of compound 84 as an excellent A AR antagonist (A K = 54 nM, A /A fold < 0.1, cAMP IC = 0.3 µM) that exhibited significant improvement in anti-PD efficacy in the HIC rat model.
[Mh] Termos MeSH primário: Antagonistas do Receptor A2 de Adenosina/química
Antagonistas do Receptor A2 de Adenosina/farmacologia
Avaliação Pré-Clínica de Medicamentos/métodos
Doença de Parkinson/tratamento farmacológico
Receptor A2A de Adenosina/metabolismo
[Mh] Termos MeSH secundário: Antagonistas do Receptor A2 de Adenosina/uso terapêutico
Animais
Catalepsia/induzido quimicamente
Catalepsia/tratamento farmacológico
Haloperidol/farmacologia
Masculino
Modelos Moleculares
Conformação Molecular
Ratos
Ratos Wistar
Interface Usuário-Computador
[Pt] Tipo de publicação:COMPARATIVE STUDY; JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Adenosine A2 Receptor Antagonists); 0 (Receptor, Adenosine A2A); J6292F8L3D (Haloperidol)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:180227
[Lr] Data última revisão:
180227
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170503
[St] Status:MEDLINE
[do] DOI:10.1021/acs.jcim.7b00188



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