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1.
Medicine (Baltimore) ; 99(51): e23803, 2020 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-33371155

RESUMO

INTRODUCTION: Post-stroke cognitive impairment (PSCI), which has a high morbidity, is closely associated with the recurrence and rehabilitation of ischemic stroke. There are 2 different stages of PSCI, including post-stroke cognitive impairment with no dementia (PSCIND) and post-stroke dementia (PSD). The latter has a significantly higher mortality rate than the previous one. Therefore, preventing the onset of PSD is of vital importance. However, there is no unequivocally effective prevention or treatment for PSCI, except intensive secondary prevention of stroke. The primary aim of this protocol is to explore whether acupuncture can improve cognitive function of patients with PSCIND and reduce the chances of developing PSD. On this bias, we also want to explore its possible mechanisms. METHODS AND ANALYSIS: A prospective, multicenter, large sample, randomized controlled trial will be conducted. A total of 360 eligible patients will be recruited from 5 different hospitals and randomly allocated into the acupuncture group (AG), sham acupuncture group (NAG), and waiting-list group (WLG) in a 1:1:1 ratio. The intervention period of NAG and AG will last 3 months (30 minutes per day, 3 times per week). Primary and secondary outcomes will be measured at baseline, 12 weeks (at the end of the intervention), 24 weeks (after the 12-week follow-up period), and 36 weeks (after the 24-week follow-up period). Resting-state and task-state functional MRI will be conducted at baseline and 12 weeks. ETHICS AND DISSEMINATION: The ethic committee of First Teaching Hospital of University of Traditional Chinese Medicine approved the study. Study results will be first informed to each participant and later disseminated to researchers, and the general public through courses, presentations and the internet, regardless of the magnitude or direction of effect. The results will also be documented in a published peer-reviewed academic journal. REGISTRATION: We have registered at ClinicalTrials.gov(ChiCTR2000033801).


Assuntos
Terapia por Acupuntura/normas , Disfunção Cognitiva/terapia , Acidente Vascular Cerebral/complicações , Terapia por Acupuntura/métodos , Terapia por Acupuntura/estatística & dados numéricos , China , Disfunção Cognitiva/etiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Estudos Prospectivos , Estatísticas não Paramétricas , Acidente Vascular Cerebral/terapia , Reabilitação do Acidente Vascular Cerebral/métodos , Fatores de Tempo , Resultado do Tratamento
2.
Medicine (Baltimore) ; 99(52): e23456, 2020 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-33350728

RESUMO

BACKGROUND: Depression is a common disease which occurs after stroke, affecting approximately one third of stroke survivors at any 1 time after stroke (compared with 5%-13% of adults without stroke), with a cumulative incidence of 55%. Acupuncture, which has a long history in China, is the generic name of different kinds of acupuncture therapies, including manual acupuncture (MA), electroacupuncture (EA), fire needle (FN), dry needling (DN), and so on. Clinical studies have shown that acupuncture has a good therapeutic effect on post stroke depression (PSD), but the evidence-based medicine of it is insufficient. The purpose of this study is to systematically evaluate the efficacy of different kinds of acupuncture therapies in the treatment of PSD, and to provide evidence-based basis for the clinical application of acupuncture in the treatment of PSD. METHODS: A systematic search will be performed on English databases (PubMed, The Cochrane Library, Medline, Embase) and Chinese databases (China National Knowledge Infrastructure (CNKI), WanFang Data, VIP and Chinese biomedical databases). The retrieval time limit will be from the establishment of the database to August 2020. Two researchers will independently screen the literatures, extract data, and evaluate the quality of the included studies. Bayesian network analysis will be conducted by using STATA V.14.0 and ADDIS V.1.16.7. RESULTS: In this study, the efficacy of different kinds of acupuncture therapies in the treatment of PSD will be evaluated by the degree of reduction in depression, total numbers of adverse events, quality of life indices, improvement of social and life functions and the expression of nerve cell factors. CONCLUSIONS: This study will provide reliable evidence-based evidence for the clinical application of acupuncture in PSD.


Assuntos
Terapia por Acupuntura/métodos , Depressão/etiologia , Depressão/terapia , Metanálise como Assunto , Metanálise em Rede , Projetos de Pesquisa , Acidente Vascular Cerebral/complicações , Teorema de Bayes , Humanos
3.
Nat Commun ; 10(1): 5751, 2019 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-31848352

RESUMO

The poly(ADP-ribose) polymerase, PARP1, plays a key role in maintaining genomic integrity by detecting DNA damage and mediating repair. γH2A.X is the primary histone marker for DNA double-strand breaks and PARP1 localizes to H2A.X-enriched chromatin damage sites, but the basis for this association is not clear. We characterize the kinetics of PARP1 binding to a variety of nucleosomes harbouring DNA double-strand breaks, which reveal that PARP1 associates faster with (γ)H2A.X- versus H2A-nucleosomes, resulting in a higher affinity for the former, which is maximal for γH2A.X-nucleosome that is also the activator eliciting the greatest poly-ADP-ribosylation catalytic efficiency. The enhanced activities with γH2A.X-nucleosome coincide with increased accessibility of the DNA termini resulting from the H2A.X-Ser139 phosphorylation. Indeed, H2A- and (γ)H2A.X-nucleosomes have distinct stability characteristics, which are rationalized by mutational analysis and (γ)H2A.X-nucleosome core crystal structures. This suggests that the γH2A.X epigenetic marker directly facilitates DNA repair by stabilizing PARP1 association and promoting catalysis.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Reparo do DNA/genética , Histonas/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Nucleossomos/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/isolamento & purificação , Biocatálise , Cristalografia por Raios X , Quebras de DNA de Cadeia Dupla , Epigênese Genética , Histonas/síntese química , Histonas/ultraestrutura , Modelos Moleculares , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/isolamento & purificação , Nucleossomos/ultraestrutura , Poli(ADP-Ribose) Polimerase-1/genética , Poli(ADP-Ribose) Polimerase-1/isolamento & purificação , Poli ADP Ribosilação/genética , Proteínas Recombinantes/genética , Proteínas Recombinantes/isolamento & purificação , Proteínas Recombinantes/metabolismo
4.
Org Lett ; 20(24): 7790-7793, 2018 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-30517009

RESUMO

A previously undescribed reaction involving the formation of a thiazolidin-5-imine linkage was developed for bioconjugation. Being highly specific and operating in aqueous media, this simple condensation reaction is used to chemoselectively label peptides, proteins, and living cells under physiological conditions without the need to use toxic catalysts or reducing reagents.


Assuntos
Corantes Fluorescentes/química , Iminas/química , Imagem Óptica , Proteínas/análise , Tiazolidinas/química , Corantes Fluorescentes/síntese química , Células HeLa , Humanos , Iminas/síntese química , Modelos Moleculares , Estrutura Molecular , Coloração e Rotulagem , Tiazolidinas/síntese química
5.
J Chromatogr A ; 1570: 109-115, 2018 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-30098730

RESUMO

This paper describes the development of a novel gas chromatography-mass spectrometry-selected ion monitoring (GC/MS-SIM) method for the determination of trace water contents of organic solvents, using the characteristic m/z 18, m/z 17, and m/z 16 ions of H2O as the qualitative ion and the m/z 18 ion as the quantifier ion. The accuracy and precision of this method were validated. An excellent linear correlation was obtained for trace water contents between 0 and 0.5217 wt%, with a correlation coefficient (R2) of 0.9999, in addition to spike recoveries of 82.6-112.6%, and relative standard deviations (n = 6) of 0.4-7.2%. The limit of detection (S/N = 3) and limit of quantitation (S/N = 10) for the trace water contents of organic solvents were 0.0005% wt% and 0.0016% wt%, respectively.The analytical results confirmed that this method was useful for determining the trace water contents of organic solvents, because it has a low detection limit and wide linear range. It requires only small amounts of the samples and enables sample batch analysis. It is very environmentally friendly and saves reagents.


Assuntos
Cromatografia Gasosa-Espectrometria de Massas/métodos , Compostos Orgânicos/análise , Solventes/química , Água/análise , Limite de Detecção , Compostos Orgânicos/química , Água/química
6.
Bioconjug Chem ; 29(7): 2170-2175, 2018 07 18.
Artigo em Inglês | MEDLINE | ID: mdl-29870654

RESUMO

Backbone-cyclic proteins are of great scientific and therapeutic interest owing to their higher stability over their linear counterparts. Modification of such cyclic proteins at a selected site would further enhance their versatility. Here we report a chemoenzymatic strategy to engineer site-selectively modified cyclic proteins by combining butelase-mediated macrocyclization with the genetic code expansion methodology. Using this strategy, we prepared a cyclic protein which was modified with biotin or a cell-penetrating peptide at a genetically incorporated noncanonical amino acid, making the cyclization-stabilized protein further amenable for site-specific immobilization and intracellular delivery. Our results point to a new avenue to engineering novel cyclic proteins with improved physicochemical and pharmacological properties for potential applications in biotechnology and medicine.


Assuntos
Permeabilidade da Membrana Celular , Peptídeos Penetradores de Células/genética , Peptídeos Cíclicos/metabolismo , Engenharia de Proteínas/métodos , Aminoácidos/metabolismo , Biotina , Ciclização , Código Genético , Peptídeos Cíclicos/genética
7.
J Med Chem ; 61(4): 1622-1635, 2018 02 22.
Artigo em Inglês | MEDLINE | ID: mdl-29400470

RESUMO

A noninvasive topical ocular therapy for the treatment of neovascular or "wet" age-related macular degeneration would provide a patient administered alternative to the current standard of care, which requires physician administered intravitreal injections. This manuscript describes a novel strategy for the use of in vivo models of choroidal neovascularization (CNV) as the primary means of developing SAR related to efficacy from topical administration. Ultimately, this effort led to the discovery of acrizanib (LHA510), a small-molecule VEGFR-2 inhibitor with potency and efficacy in rodent CNV models, limited systemic exposure after topical ocular administration, multiple formulation options, and an acceptable rabbit ocular PK profile.


Assuntos
Administração Tópica , Indóis/administração & dosagem , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Degeneração Macular Exsudativa/tratamento farmacológico , Animais , Neovascularização de Coroide , Descoberta de Drogas , Indóis/farmacocinética , Indóis/uso terapêutico , Soluções Oftálmicas , Inibidores de Proteínas Quinases , Pirazóis/farmacocinética , Pirazóis/uso terapêutico , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Coelhos , Roedores , Relação Estrutura-Atividade
8.
Angew Chem Int Ed Engl ; 56(27): 7822-7825, 2017 06 26.
Artigo em Inglês | MEDLINE | ID: mdl-28524544

RESUMO

Butelase-mediated ligation (BML) can be used to modify live bacterial cell surfaces with diverse cargo molecules. Surface-displayed butelase recognition motif NHV was first introduced at the C-terminal end of the anchoring protein OmpA on E. coli cells. This then served as a handle of BML for the functionalization of E. coli cell surfaces with fluorescein and biotin tags, a tumor-associated monoglycosylated peptide, and mCherry protein. The cell-surface ligation reaction was achieved at low concentrations of butelase and the labeling substrates. Furthermore, the fluorescein-labeled bacterial cells were used to show the interactions with cultured HeLa cells and with macrophages in live transgenic zebrafish, capturing the latter's powerful phagocytic effect in action. Together these results highlight the usefulness of butelase 1 in live bacterial cell surface engineering for novel applications.


Assuntos
Escherichia coli/metabolismo , Glicopeptídeos/metabolismo , Ligases/metabolismo , Proteínas de Plantas/metabolismo , Sequência de Aminoácidos , Animais , Animais Geneticamente Modificados , Clitoria/enzimologia , Escherichia coli/química , Glicopeptídeos/química , Células HeLa , Interações Hospedeiro-Patógeno , Humanos , Lisossomos/química , Lisossomos/metabolismo , Macrófagos/citologia , Macrófagos/metabolismo , Microscopia Confocal , Peixe-Zebra
9.
Org Biomol Chem ; 15(12): 2491-2496, 2017 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-28170021

RESUMO

Peptide Weinreb amide derivatives with an N-substituted mercaptoethyl group are designed as thioester precursors for native chemical ligation. We show that these amides undergo rapid ligation with a cysteinyl peptide under normal NCL conditions to form various Xaa-Cys peptide bonds, including the difficult Val-Cys junction. Facile synthesis of the Weinreb amide linkers allows easy access to this new type of peptide thioester precursor by standard Fmoc solid phase synthesis.


Assuntos
Amidas/química , Ésteres/química , Peptídeos/química , Compostos de Sulfidrila/química , Amidas/síntese química , Estrutura Molecular , Peptídeos/síntese química
10.
J Pak Med Assoc ; 66(4): 368-72, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27122258

RESUMO

OBJECTIVE: To investigate in vitro effects of nicotine on the non-small-cell lung cancer line A549. METHODS: The case-control study was conducted at the First Affiliated Hospital of Nanchang University from 1st January to 30th June, 2014 and comprised A549 cells which were treated with a series of concentrations of nicotine (0.01 µM, 0.1 µM, 1 µM and 10 µM) for 24 hours. Control cells were incubated under the same conditions without the addition of nicotine. Cell growth was detected by monotetrazolium salt [3-(4, 5-dimethyl-2-thiazolyl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium] assay. Cell apoptosis was detected by Haematoxylin and Eosin staining, immunofluorescence analysis of Filamentous actin and electron microscope observation. RESULTS: Nicotine had no significant effect on A549 cell growth at the dose of 0.01µM (p>0.05), but had significant growth inhibitory effects at the doses of 0.1µM, 1µM and 10µM (p< 0.05 each). A significant decrease in cell numbers was observed on staining (p< 0.05). Significant changes in the size and shape of cells and concomitant changes in cytoskeletons and organelles were observed by immunofluorescence and electron microscope observation (p< 0.05). CONCLUSIONS: The growth inhibitory effects of nicotine on A549 cells were found to be dose-dependent.


Assuntos
Células A549/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Carcinoma Pulmonar de Células não Pequenas , Proliferação de Células/efeitos dos fármacos , Neoplasias Pulmonares , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Células A549/citologia , Células A549/ultraestrutura , Estudos de Casos e Controles , Humanos , Técnicas In Vitro , Microscopia Eletrônica , Microscopia de Fluorescência
11.
Guang Pu Xue Yu Guang Pu Fen Xi ; 36(12): 4088-93, 2016 Dec.
Artigo em Chinês | MEDLINE | ID: mdl-30256580

RESUMO

To study the thermodynamics properties of the solar atmosphere with different height distribution, the imaging grating spectrometer with excellent image quality is one of the important tools to achieve this goal. However, the atmosphere turbulence can not be avoided for the imaging grating spectrometer installed in the ground-based solar telescope, and the imaging properties of the grating spectrometer will influenced by the wavefront aberration generalized by the atmosphere turbulence and the wavefront aberration generalized by the optical system adjusting errors and the optical element manufacturing errors. The atmospheric turbulence can be effectively compensated by the Adaptive Optics. To correct the wavefront aberrations of the optical system, a correction method based on Adaptive Optics is proposed, and the experiment validation is carried out to verify the feasibility of the method. The results demonstrate that the correction method proposed can effectively correct the wavefront aberration generalized by the atmosphere turbulence and the optical system aberration. The RMS value is roughly equal to 0.025λ after the Adaptive Optics correction. Besides, it has the virtue of lower the requirement of optical system adjusting errors and optical elements manufacturing errors.

12.
J Med Chem ; 58(23): 9273-86, 2015 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-26568411

RESUMO

The benefit of intravitreal anti-VEGF therapy in treating wet age-related macular degeneration (AMD) is well established. Identification of VEGFR-2 inhibitors with optimal ADME properties for an ocular indication provides opportunities for dosing routes beyond intravitreal injection. We employed a high-throughput in vivo screening strategy with rodent models of choroidal neovascularization and iterative compound design to identify VEGFR-2 inhibitors with potential to benefit wet AMD patients. These compounds demonstrate preferential ocular tissue distribution and efficacy after oral administration while minimizing systemic exposure.


Assuntos
Inibidores da Angiogênese/química , Inibidores da Angiogênese/uso terapêutico , Neovascularização de Coroide/tratamento farmacológico , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Receptor 2 de Fatores de Crescimento do Endotélio Vascular/antagonistas & inibidores , Degeneração Macular Exsudativa/tratamento farmacológico , Administração Oral , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacocinética , Animais , Corioide/efeitos dos fármacos , Corioide/patologia , Neovascularização de Coroide/patologia , Feminino , Humanos , Injeções Intravítreas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/farmacocinética , Pirimidinas/administração & dosagem , Pirimidinas/química , Pirimidinas/farmacocinética , Pirimidinas/uso terapêutico , Ratos , Degeneração Macular Exsudativa/patologia
13.
PLoS One ; 9(10): e111472, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-25343517

RESUMO

Proteins that are post-translationally adducted with 2-(ω-carboxyethyl)pyrrole (CEP) have been proposed to play a pathogenic role in age-related macular degeneration, by inducing angiogenesis in a Toll Like Receptor 2 (TLR2)-dependent manner. We have investigated the involvement of CEP adducts in angiogenesis and TLR activation, to assess the therapeutic potential of inhibiting CEP adducts and TLR2 for ocular angiogenesis. As tool reagents, several CEP-adducted proteins and peptides were synthetically generated by published methodology and adduction was confirmed by NMR and LC-MS/MS analyses. Structural studies showed significant changes in secondary structure in CEP-adducted proteins but not the untreated proteins. Similar structural changes were also observed in the treated unadducted proteins, which were treated by the same adduction method except for one critical step required to form the CEP group. Thus some structural changes were unrelated to CEP groups and were artificially induced by the synthesis method. In biological studies, the CEP-adducted proteins and peptides failed to activate TLR2 in cell-based assays and in an in vivo TLR2-mediated retinal leukocyte infiltration model. Neither CEP adducts nor TLR agonists were able to induce angiogenesis in a tube formation assay. In vivo, treatment of animals with CEP-adducted protein had no effect on laser-induced choroidal neovascularization. Furthermore, in vivo inactivation of TLR2 by deficiency in Myeloid Differentiation factor 88 (Myd88) had no effect on abrasion-induced corneal neovascularization. Thus the CEP-TLR2 axis, which is implicated in other wound angiogenesis models, does not appear to play a pathological role in a corneal wound angiogenesis model. Collectively, our data do not support the mechanism of action of CEP adducts in TLR2-mediated angiogenesis proposed by others.


Assuntos
Neovascularização Patológica/metabolismo , Pirróis/metabolismo , Receptor 2 Toll-Like/metabolismo , Animais , Neovascularização de Coroide/patologia , Modelos Animais de Doenças , Células HEK293 , Humanos , Lasers , Leucócitos/metabolismo , Camundongos Endogâmicos C57BL , Retina/metabolismo , Retina/patologia , Receptor 2 Toll-Like/agonistas
14.
ACS Med Chem Lett ; 4(12): 1203-7, 2013 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-24900631

RESUMO

Aldosterone is a key signaling component of the renin-angiotensin-aldosterone system and as such has been shown to contribute to cardiovascular pathology such as hypertension and heart failure. Aldosterone synthase (CYP11B2) is responsible for the final three steps of aldosterone synthesis and thus is a viable therapeutic target. A series of imidazole derived inhibitors, including clinical candidate 7n, have been identified through design and structure-activity relationship studies both in vitro and in vivo. Compound 7n was also found to be a potent inhibitor of 11ß-hydroxylase (CYP11B1), which is responsible for cortisol production. Inhibition of CYP11B1 is being evaluated in the clinic for potential treatment of hypercortisol diseases such as Cushing's syndrome.

15.
Bioorg Med Chem Lett ; 21(5): 1447-51, 2011 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-21300545

RESUMO

The synthesis and preliminary studies of the SAR of novel 3,5-diarylazole inhibitors of Protein Kinase D (PKD) are reported. Notably, optimized compounds in this class have been found to be active in cellular assays of phosphorylation-dependant HDAC5 nuclear export, orally bioavailable, and highly selective versus a panel of additional putative histone deacetylase (HDAC) kinases. Therefore these compounds could provide attractive tools for the further study of PKD/HDAC5 signaling.


Assuntos
Azóis/farmacologia , Proteína Quinase C/antagonistas & inibidores , Inibidores de Proteínas Quinases/farmacologia , Administração Oral , Animais , Azóis/síntese química , Azóis/química , Azóis/farmacocinética , Disponibilidade Biológica , Histona Desacetilases/metabolismo , Concentração Inibidora 50 , Estrutura Molecular , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacocinética , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Relação Estrutura-Atividade
16.
J Med Chem ; 53(15): 5400-21, 2010 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-20684591

RESUMO

A novel 2,6-naphthyridine was identified by high throughput screen (HTS) as a dual protein kinase C/D (PKC/PKD) inhibitor. PKD inhibition in the heart was proposed as a potential antihypertrophic mechanism with application as a heart failure therapy. As PKC was previously identified as the immediate upstream activator of PKD, PKD vs PKC selectivity was essential to understand the effect of PKD inhibition in models of cardiac hypertrophy and heart failure. The present study describes the modification of the HTS hit to a series of prototype pan-PKD inhibitors with routine 1000-fold PKD vs PKC selectivity. Example compounds inhibited PKD activity in vitro, in cells, and in vivo following oral administration. Their effects on heart morphology and function are discussed herein.


Assuntos
Aminopiridinas/síntese química , Naftiridinas/síntese química , Proteína Quinase C/antagonistas & inibidores , Transporte Ativo do Núcleo Celular , Administração Oral , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/química , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/tratamento farmacológico , Cardiomegalia/patologia , Núcleo Celular/metabolismo , Histona Desacetilases/metabolismo , Isoenzimas/antagonistas & inibidores , Masculino , Modelos Moleculares , Células Musculares/efeitos dos fármacos , Células Musculares/metabolismo , Células Musculares/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Naftiridinas/farmacocinética , Naftiridinas/farmacologia , Fosforilação , Ligação Proteica , Ratos , Ratos Endogâmicos Dahl , Ratos Sprague-Dawley , Relação Estrutura-Atividade
17.
J Med Chem ; 53(15): 5422-38, 2010 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-20684592

RESUMO

The synthesis and biological evaluation of potent and selective PKD inhibitors are described herein. The compounds described in the present study selectively inhibit PKD among other putative HDAC kinases. The PKD inhibitors of the present study blunt phosphorylation and subsequent nuclear export of HDAC4/5 in response to diverse agonists. These compounds further establish the central role of PKD as an HDAC4/5 kinase and enhance the current understanding of cardiac myocyte signal transduction. The in vivo efficacy of a representative example compound on heart morphology is reported herein.


Assuntos
2,2'-Dipiridil/análogos & derivados , Aminopiridinas/síntese química , Naftiridinas/síntese química , Piperazinas/síntese química , Proteína Quinase C/antagonistas & inibidores , 2,2'-Dipiridil/síntese química , 2,2'-Dipiridil/farmacocinética , 2,2'-Dipiridil/farmacologia , Transporte Ativo do Núcleo Celular , Administração Oral , Aminopiridinas/farmacocinética , Aminopiridinas/farmacologia , Animais , Anti-Hipertensivos/síntese química , Anti-Hipertensivos/farmacocinética , Anti-Hipertensivos/farmacologia , Pressão Sanguínea/efeitos dos fármacos , Cardiomegalia/tratamento farmacológico , Cardiomegalia/enzimologia , Cardiomegalia/patologia , Núcleo Celular/metabolismo , Histona Desacetilases/metabolismo , Isoenzimas/antagonistas & inibidores , Masculino , Modelos Moleculares , Células Musculares/efeitos dos fármacos , Células Musculares/metabolismo , Células Musculares/patologia , Miocárdio/metabolismo , Miocárdio/patologia , Naftiridinas/farmacocinética , Naftiridinas/farmacologia , Fosforilação , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ligação Proteica , Ratos , Ratos Endogâmicos Dahl , Ratos Sprague-Dawley , Relação Estrutura-Atividade
18.
Bioorg Med Chem Lett ; 20(15): 4324-7, 2010 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-20615692

RESUMO

Aldosterone, the final component of the renin-angiotensin-aldosterone system, plays an important role in the pathophysiology of hypertension and congestive heart failure. Aldosterone synthase (CYP11B2) catalyzes the last three steps of aldosterone biosynthesis, and as such appears to be a target for the treatment of these disorders. A sulfonamide-imidazole scaffold has proven to be a potent inhibitor of CYP11B2. Furthermore, this scaffold can achieve high levels of selectivity for CYP11B2 over CYP11B1, a key enzyme in the biosynthesis of cortisol.


Assuntos
Citocromo P-450 CYP11B2/antagonistas & inibidores , Inibidores Enzimáticos/química , Esteroide 11-beta-Hidroxilase/antagonistas & inibidores , Citocromo P-450 CYP11B2/metabolismo , Avaliação Pré-Clínica de Medicamentos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Imidazóis/síntese química , Imidazóis/química , Imidazóis/farmacologia , Esteroide 11-beta-Hidroxilase/metabolismo , Sulfonamidas/síntese química , Sulfonamidas/química , Sulfonamidas/farmacologia
19.
FEBS Lett ; 584(3): 631-7, 2010 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-20018189

RESUMO

Class IIa histone deacetylases (HDACs) repress genes involved in pathological cardiac hypertrophy. The anti-hypertrophic action of class IIa HDACs is overcome by signals that promote their phosphorylation-dependent nuclear export. Several kinases have been shown to phosphorylate class IIa HDACs, including calcium/calmodulin-dependent protein kinase (CaMK), protein kinase D (PKD) and G protein-coupled receptor kinase (GRK). However, the identity of the kinase(s) responsible for phosphorylating class IIa HDACs during cardiac hypertrophy has remained controversial. We describe a novel and selective small molecule inhibitor of PKD, bipyridyl PKD inhibitor (BPKDi). BPKDi blocks signal-dependent phosphorylation and nuclear export of class IIa HDACs in cardiomyocytes and concomitantly suppresses hypertrophy of these cells. These studies define PKD as a principal cardiac class IIa HDAC kinase.


Assuntos
Histona Desacetilases/metabolismo , Miocárdio/enzimologia , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Animais , Immunoblotting , Imunoprecipitação , Fosforilação , Transporte Proteico , Ratos , Ratos Sprague-Dawley
20.
J Comb Chem ; 9(6): 1177-87, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17824665

RESUMO

Due to their diverse range of biological activities, imidazoheterocycles are recognized as privileged structures making these structural motifs attractive targets for library preparation. We report herein the synthesis of a sizable collection of imidazo[1,2- a]heterocycle scaffolds well-suited for divergent library preparation by virtue of amine functional handles with diverse positioning and connectivities. Partial reduction of imidazo[1,2- a]pyrazines to the tetrahydroimidazo[1,2- a]pyrazines and regiospecific Mannich-type bond formation at the C-3 of imidazo[1,2- a]pyridine under mild conditions achieved additional topological and connective diversity within the scaffold collection. Subsequent parallel reaction of the functionalized imidazoheterocycles with polystyrene-tetrafluorophenol esters and sulfonates produced a 7500 compound library in high purity.


Assuntos
Aldeídos/química , Aminas/química , Técnicas de Química Combinatória , Compostos Heterocíclicos/síntese química , Imidazóis/síntese química , Nitrilos/química , Química Farmacêutica , Cromatografia Líquida de Alta Pressão , Ésteres/química , Modelos Químicos , Fenóis/química , Poliestirenos/química , Piridinas/química , Ácidos Sulfônicos/química
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