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1.
ACS Med Chem Lett ; 11(12): 2389-2396, 2020 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-33335661

RESUMO

Amino-quinazoline BRaf kinase inhibitor 2 was identified from a library screen as a modest inhibitor of the unfolded protein response (UPR) regulating potential anticancer target IRE1α. A combination of crystallographic and conformational considerations were used to guide structure-based attenuation of BRaf activity and optimization of IRE1α potency. Quinazoline 6-position modifications were found to provide up to 100-fold improvement in IRE1α cellular potency but were ineffective at reducing BRaf activity. A salt bridge contact with Glu651 in IRE1α was then targeted to build in selectivity over BRaf which instead possesses a histidine in this position (His539). Torsional angle analysis revealed that the quinazoline hinge binder core was ill-suited to accommodate the required conformation to effectively reach Glu651, prompting a change to the thienopyrimidine hinge binder. Resulting analogues such as 25 demonstrated good IRE1α cellular potency and imparted more than 1000-fold decrease in BRaf activity.

3.
J Forensic Sci ; 62(3): 668-673, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28000209

RESUMO

While it is recognized that veterans have increased rates of depression, post-traumatic stress disorder (PTSD), suicide, and substance use disorders, rates of homicide and unintentional injury deaths in veterans have been minimally investigated. We evaluated all non-natural deaths in New Mexico veterans between 2002 and 2011 in comparison with non-natural deaths among non-veterans. We reviewed all decedents in New Mexico with a history of military service and investigated by the medical examiner, excluding natural deaths and deaths due to fall from standing height. The most common manner of death was unintentional injury (62%), most of these deaths due to motor vehicle accidents (29%) followed by unintentional overdose (26%). Suicide rates among veterans were consistently higher than the general population. The most common mechanism of suicide in men was gunshot wound (72%), and intentional overdose in women (49%). Services are needed for veterans that are tailored to all ages and both sexes.


Assuntos
Causas de Morte , Veteranos/estatística & dados numéricos , Acidentes/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Médicos Legistas , Overdose de Drogas/mortalidade , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , New Mexico/epidemiologia , Estudos Retrospectivos , Distribuição por Sexo , Suicídio/estatística & dados numéricos , Ferimentos e Lesões/mortalidade , Adulto Jovem
4.
Hum Pathol ; 45(12): 2502-6, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25288237

RESUMO

The most common clinical syndromes presenting with paragangliomas and/or pheochromocytomas as their endocrine components are multiple endocrine neoplasia type 2, neurofibromatosis, Von Hippel-Lindau syndrome, Carney-Stratakis syndrome, Carney triad, and the recently described hereditary paraganglioma syndrome. Only Carney triad is known to also present with adrenocortical adenomas, currently representing the only described syndrome in which all 3 of the aforementioned tumors are found together. In most cases, prototypical lesions of the triad such as gastrointestinal stromal tumor and pulmonary chondromas are also seen. We present a case of a young woman with synchronous paragangliomas, adrenal/extra-adrenal cortical neoplasms, and pheochromocytoma without genetic mutations for multiple endocrine neoplasia 2, Von Hippel-Lindau syndrome, neurofibromatosis, and succinate dehydrogenase. We speculate that this represents a previously undescribed presentation of Carney triad and, at the very least, indicates the need for monitoring for the development of other tumors of the triad.


Assuntos
Neoplasias do Córtex Suprarrenal/patologia , Condroma/patologia , Leiomiossarcoma/patologia , Neoplasias Pulmonares/patologia , Neoplasias Primárias Múltiplas/patologia , Paraganglioma Extrassuprarrenal/patologia , Paraganglioma/patologia , Feocromocitoma/patologia , Neoplasias Gástricas/patologia , Neoplasias do Córtex Suprarrenal/cirurgia , Condroma/cirurgia , Feminino , Humanos , Leiomiossarcoma/cirurgia , Neoplasias Pulmonares/cirurgia , Neoplasias Primárias Múltiplas/cirurgia , Paraganglioma/cirurgia , Paraganglioma Extrassuprarrenal/cirurgia , Feocromocitoma/cirurgia , Neoplasias Gástricas/cirurgia , Adulto Jovem
5.
J Med Chem ; 57(5): 1770-6, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-23506530

RESUMO

Given the emergence of resistance observed for the current clinical-stage hepatitis C virus (HCV) NS3 protease inhibitors, there is a need for new inhibitors with a higher barrier to resistance. We recently reported our rational approach to the discovery of macrocyclic acylsulfonamides as HCV protease inhibitors addressing potency against clinically relevant resistant variants. Using X-ray crystallography of HCV protease variant/inhibitor complexes, we shed light on the complex structural mechanisms by which the D168V and R155K residue mutations confer resistance to NS3 protease inhibitors. Here, we disclose SAR investigation and ADME/PK optimization leading to the identification of inhibitors with significantly improved potency against the key resistant variants and with increased liver partitioning.


Assuntos
Fígado/metabolismo , Inibidores de Proteases/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Cristalografia por Raios X , Humanos , Espectroscopia de Ressonância Magnética , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Espectrometria de Massas por Ionização por Electrospray
6.
Bioorg Med Chem Lett ; 23(15): 4447-52, 2013 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-23773863

RESUMO

A number of potent peptidic inhibitors of the NS3 protease have been described in the literature based on a substrate-based approach. In an on-going effort to reduce the peptidic character of this class of inhibitors, two novel series of analogs have been prepared in which the usual P3 amino acid residue is replaced by a succinamide fragment. This new backbone modification not only reduces the peptidic nature of traditional inhibitors but also provides new SAR opportunities for the capping group. Optimization of each of these two series resulted in inhibitors with sub-nanomolar potencies.


Assuntos
Amidas/química , Hepacivirus/enzimologia , Inibidores de Proteases/química , Succinatos/química , Proteínas não Estruturais Virais/antagonistas & inibidores , Amidas/farmacocinética , Animais , Cães , Meia-Vida , Haplorrinos , Humanos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Inibidores de Proteases/farmacocinética , Ratos , Relação Estrutura-Atividade , Succinatos/farmacocinética , Proteínas não Estruturais Virais/metabolismo
7.
Bioorg Med Chem Lett ; 23(14): 4267-71, 2013 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-23735741

RESUMO

In this report we describe the synthesis and evaluation of diverse 4-arylproline analogs as HCV NS3 protease inhibitors. Introduction of this novel P2 moiety opened up new SAR and, in combination with a synthetic approach providing a versatile handle, allowed for efficient exploitation of this novel series of NS3 protease inhibitors. Multiple structural modifications of the aryl group at the 4-proline, guided by structural analysis, led to the identification of analogs which were very potent in both enzymatic and cell based assays. The impact of this systematic SAR on different drug properties is reported.


Assuntos
Antivirais/síntese química , Hepacivirus/enzimologia , Prolina/análogos & derivados , Inibidores de Proteases/síntese química , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/química , Antivirais/farmacocinética , Sítios de Ligação , Desenho de Fármacos , Meia-Vida , Hepacivirus/fisiologia , Simulação de Acoplamento Molecular , Prolina/síntese química , Prolina/farmacocinética , Inibidores de Proteases/química , Inibidores de Proteases/farmacocinética , Estrutura Terciária de Proteína , Ratos , Relação Estrutura-Atividade , Proteínas não Estruturais Virais/metabolismo , Replicação Viral/efeitos dos fármacos
8.
J Biotechnol ; 163(1): 1-9, 2013 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-23108027

RESUMO

Arsenic is a toxic metalloid and recognized carcinogen. Arsenate and arsenite are the most common arsenic species available for uptake by plants. As an inorganic phosphate (Pi) analog, arsenate is acquired by plant roots through endogenous Pi transport systems. Inside the cell, arsenate is reduced to the thiol-reactive form arsenite. Glutathione (GSH)-conjugates of arsenite may be extruded from the cell or sequestered in vacuoles by members of the ATP-binding cassette (ABC) family of transporters. In the present study we sought to enhance both plant arsenic uptake through Pi transporter overexpression, and plant arsenic tolerance through ABC transporter overexpression. We demonstrate that Arabidopsis thaliana plants overexpressing the high-affinity Pi transporter family members, AtPht1;1 or AtPht1;7, are hypersensitive to arsenate due to increased arsenate uptake. These plants do not exhibit increased sensitivity to arsenite. Co-overexpression of the yeast ABC transporter YCF1 in combination with AtPht1;1 or AtPht1;7 suppresses the arsenate-sensitive phenotype while further enhancing arsenic uptake. Taken together, our results support an arsenic transport mechanism in which arsenate uptake is increased through Pi transporter overexpression, and arsenic tolerance is enhanced through YCF1-mediated vacuolar sequestration. This work substantiates the viability of coupling enhanced uptake and vacuolar sequestration as a means for developing a prototypical engineered arsenic hyperaccumulator.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Arabidopsis/metabolismo , Arsênio/metabolismo , Biotecnologia/métodos , Plantas Geneticamente Modificadas/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Arabidopsis/genética , Arsênio/análise , Arsênio/química , Arsenicais/química , Arsenicais/metabolismo , Biodegradação Ambiental , Glutationa/metabolismo , Fenótipo , Plantas Geneticamente Modificadas/genética , Proteínas de Saccharomyces cerevisiae/genética
9.
Plant Physiol ; 159(2): 548-57, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22505730

RESUMO

Our goal was to create a DNA chip that is as easy, convenient, and inexpensive as an agarose gel. For a first-generation solution, we describe a low-cost, easy-to-use de novo synthesis oligonucleotide microarray technology that draws on the inherent flexibility of the maskless array synthesizer for in situ synthesis of thousands of photolithographically produced oligonucleotides covalently attached to a microscope slide. The method involves physically subdividing the slide into 1 × 1 mm millichips that are hybridized to fluorescent RNA or DNA of biological origin, in a microfuge tube at an ordinary laboratory benchtop, rather than in dedicated hybridization chambers. Fluorescence intensity is then measured with a standard microscope rather than sophisticated DNA chip scanners. For proof of principle, we measured changes in the transcriptome of Arabidopsis (Arabidopsis thaliana) plants induced by growth in the presence of three major environmental abiotic stresses (temperature, light, and water status), in all possible combinations. Validation by comparison with quantitative reverse transcription PCR showed a high correlation coefficient and analysis of variance indicated a high technical reproducibility. These experiments demonstrate that low-cost DNA millichips can be made and reliably used at the benchtop in a normal laboratory setting, without assistance of core facilities containing costly specialized instrumentation.


Assuntos
Arabidopsis/genética , Perfilação da Expressão Gênica/instrumentação , Análise de Sequência com Séries de Oligonucleotídeos/economia , Ácido Abscísico/farmacologia , Análise de Variância , Arabidopsis/efeitos dos fármacos , Arabidopsis/efeitos da radiação , Fluorescência , Perfilação da Expressão Gênica/economia , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Luz , Microscopia de Fluorescência , Análise de Sequência com Séries de Oligonucleotídeos/instrumentação , Análise de Sequência com Séries de Oligonucleotídeos/normas , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Temperatura , Transcriptoma , Água
10.
Int J Phytoremediation ; 13(7): 657-73, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21972493

RESUMO

Arsenic is a metalloid that occurs naturally at parts per million (ppm) levels in the earth's crust. Natural and human activities have contributed to arsenic mobilization and increased concentration in the environment, such that World Health Organization guidelines for arsenic levels in drinking water are exceeded at many locations, worldwide. This translates into an increased risk of arsenic-related illnesses for millions of people. Recent studies demonstrate that increasing thiol-sinks in transgenic plants by overexpressing the bacterial gamma-glutamylcysteine synthetase (ECS) gene results in a higher tolerance and accumulation of metals and metalloids such as cadmium, mercury, and arsenic. We used Agrobacterium-mediated transformation to genetically engineer eastern cottonwood with a bacterial ECS gene. Eastern cottonwood plants expressing ECS had elevated thiol group levels, consistent with increased ECS activity. In addition, these ECS-expressing plants had enhanced growth on levels of arsenate toxic to control plants in vitro. Furthermore, roots of ECS-expressing plants accumulated significantly more arsenic than control roots (approximately twice as much), while shoots accumulated significantly less arsenic than control shoots (approximately two-thirds as much). We discuss potential mechanisms for shifting the balance of plant arsenic distribution from root accumulation to shoot accumulation, as it pertains to arsenic phytoremediation.


Assuntos
Arsênio/metabolismo , Glutamato-Cisteína Ligase/metabolismo , Populus/efeitos dos fármacos , Populus/enzimologia , Agrobacterium tumefaciens/genética , Arabidopsis/genética , Arsênio/análise , Arsênio/toxicidade , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Biodegradação Ambiental , Escherichia coli/enzimologia , Escherichia coli/genética , Regulação Enzimológica da Expressão Gênica , Regulação da Expressão Gênica de Plantas , Glutamato-Cisteína Ligase/genética , Raízes de Plantas/química , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/crescimento & desenvolvimento , Brotos de Planta/química , Brotos de Planta/efeitos dos fármacos , Brotos de Planta/crescimento & desenvolvimento , Plantas Geneticamente Modificadas , Populus/genética , Populus/crescimento & desenvolvimento , Regiões Promotoras Genéticas/genética , Compostos de Sulfidrila/metabolismo , Técnicas de Cultura de Tecidos
11.
Org Lett ; 7(14): 2849-52, 2005 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-15987152

RESUMO

[reaction: see text] A formal enantioselective synthesis of allocolchicine and a synthesis of a C-ring analogue have been achieved by employing an intramolecular direct arylation of an aryl chloride to form the biaryl carbon-carbon bond and the seven-membered ring.


Assuntos
Colchicina/análogos & derivados , Catálise , Colchicina/síntese química , Ciclização , Hidrocarbonetos Halogenados/química , Estrutura Molecular , Paládio/química , Estereoisomerismo
12.
J Am Chem Soc ; 126(30): 9186-7, 2004 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-15281800

RESUMO

In this Communication, we describe direct arylation reactions with improved scope and catalyst activity for the intramolecular formation of biaryl compounds. This was achieved through the establishment of a highly active and robust catalyst system and the subsequent development of a novel phosphine ligand 27. The enhanced catalytic activity extends these transformations to include previously unreactive and poorly reactive substrates, and allows for very low catalyst loadings to be employed-as little as 0.1 mol %.

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