Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 8 de 8
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Food Chem Toxicol ; 71: 207-16, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24953550

RESUMO

2-Phenylaminophenylacetic acid is a widely-exploited chemical scaffold whereby notable NSAIDs such as diclofenac and lumiracoxib were derived. Yet, their clinical usage has been associated with toxicities in the liver. While some studies have attributed toxicities to the bioactivation of both drugs to reactive intermediates, the structural predisposition for toxicity, as well as relationship between this toxicity and COX inhibitory activity has not been elucidated. In this study, we aimed to address their intricate link by synthesizing compounds that possess the 2-phenylaminophenylacetic acid backbone with varying alkyl and halogen substituents at three positions critical to the COX inhibitory pharmacophore. These compounds were subjected to cytotoxicity testing on two liver cell lines of contrasting metabolic competencies. We observed higher toxicity in the more metabolically competent cell line, supporting the role of bioactivation as a prerequisite for toxicity. We have also shown that structural changes on the chemical scaffold exerted pronounced effect on liver cytotoxicity. The most lipophilic and brominated compound (24) was identified as the most cytotoxic of all the compounds. A concurrent determination of their pharmacological activity using COX inhibition assays allowed us to derive a safety profile, which showed that selectivity towards COX-2 negatively affected activity and toxicity.


Assuntos
Compostos de Anilina/toxicidade , Glicina/análogos & derivados , Testes de Toxicidade , Compostos de Anilina/química , Animais , Linhagem Celular , Glicina/química , Glicina/toxicidade , Camundongos , Relação Estrutura-Atividade
2.
J Comput Aided Mol Des ; 26(10): 1127-41, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22983491

RESUMO

Compounds known to be potent against a specific protein target may potentially contain a signature profile of common substructures that is highly correlated to their potency. These substructure profiles may be useful in enriching compound libraries or for prioritizing compounds against a specific protein target. With this objective in mind, a set of compounds with known potency against six selected kinases (2 each from 3 kinase families) was used to generate binary molecular fingerprints. Each fingerprint key represents a substructure that is found within a compound and the frequency with which the fingerprint occurs was then tabulated. Thereafter, a frequent pattern mining technique was applied with the aim of uncovering substructures that are not only well represented among known potent inhibitors but are also unrepresented among known inactive compounds and vice versa. Substructure profiles that are representative of potent inhibitors against each of the 3 kinase families were thus extracted. Based on our validation results, these substructure profiles demonstrated significant enrichment for highly potent compounds against their respective kinase targets. The advantages of using our approach over conventional methods in analyzing such datasets and its application in the mining of substructures for enriching compound libraries are presented.


Assuntos
Bases de Dados de Produtos Farmacêuticos , Desenho de Fármacos , Inibidores de Proteínas Quinases/química , Mineração de Dados , Humanos , Inibidores de Proteínas Quinases/farmacologia
4.
ChemMedChem ; 6(4): 713-24, 2011 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-21302361

RESUMO

The ability of aurones to modulate the efflux activities of ABCG2 and ABCB1 was investigated by quantifying their effects on the accumulation of pheophorbide A (PhA) in ABCG2-overexpressing MDA-MB-231/R cells and calcein AM in ABCB1-overexpressing MDCKII/MDR1 cells. Key structural features for interactions at both ABCG2 and ABCB1 are a methoxylated ring A, an intact exocyclic double bond, and the location of the carbonyl bond on ring C. Modifications on rings B and C were less critical and served primarily to moderate activity and selectivity for one or both transporters. These SAR trends were quantified by Free-Wilson analyses and are reflected in a pharmacophore model for PhA accumulation. Several compounds were found to be equipotent with fumitremorgin C (FTC) in promoting PhA accumulation, and they also demonstrated strong affinities for ABCB1. These compounds were disubstituted on ring B with methoxy or a combination of methoxy and hydroxy groups. Taken together, our findings highlight the versatility of the aurone template as a lead scaffold for the design of dual-targeting ABCG2 and ABCB1 modulators.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Antineoplásicos/farmacologia , Benzofuranos/farmacologia , Proteínas de Neoplasias/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Antineoplásicos/síntese química , Antineoplásicos/química , Benzofuranos/síntese química , Benzofuranos/química , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Humanos , Relação Estrutura-Atividade
5.
J Biol Chem ; 285(28): 21662-70, 2010 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-20452973

RESUMO

Mycobacteria store triacylglycerols (TGs) in the form of intracellular lipid droplets (LDs) during hypoxia-induced nonreplicating persistence. These bacteria are phenotypically drug-resistant and therefore are believed to be the cause for prolonged tuberculosis treatment. LDs are also associated with bacilli in tuberculosis patient sputum and hypervirulent strains. Although proteins bound to LDs are well characterized in eukaryotes, the identities and functions of such proteins have not been described in mycobacteria. Here, we have identified five proteins: Tgs1 (BCG3153c), Tgs2 (BCG3794c), BCG1169c, BCG1489c, and BCG1721, which are exclusively associated with LDs purified from hypoxic nonreplicating Mycobacterium bovis bacillus Calmette-Guérin (BCG). Disruption of genes tgs1, tgs2, BCG1169c, and BCG1489c in M. bovis BCG revealed that they are indeed involved in TG metabolism. We also characterized BCG1721, an essential bi-functional enzyme capable of promoting buildup and hydrolysis of TGs, depending on the metabolic state. Nonreplicating mycobacteria overexpressing a BCG1721 construct with an inactive lipase domain displayed a phenotype of attenuated TG breakdown and regrowth upon resuscitation. In addition, by heterologous expression in baker's yeast, these mycobacterial proteins also co-localized with LDs and complemented a lipase-deficient yeast strain, indicating that neutral lipid deposition and homeostasis in eukaryotic and prokaryotic microorganisms are functionally related. The demonstrated functional role of BCG1721 to support growth upon resuscitation makes this novel LD-associated factor a potential new target for therapeutic intervention.


Assuntos
Vacina BCG/química , Lipídeos/química , Mycobacterium bovis/metabolismo , Teste de Complementação Genética , Humanos , Hidrólise , Hipóxia , Espectrometria de Massas/métodos , Modelos Biológicos , Mutagênese Sítio-Dirigida , Mutação , Mycobacterium/metabolismo , Peptídeos/química , Estrutura Terciária de Proteína , Tripsina/química
6.
Bioorg Med Chem ; 17(21): 7562-71, 2009 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-19783149

RESUMO

A series of functionalized isoindigos structurally related to meisoindigo (1-methylisoindigo), a therapeutic agent used for the treatment of a form of leukemia, were synthesized and evaluated for antiproliferative activities on a panel of human cancer cells. Two promising compounds (1-phenpropylisoindigo and 1-(p-methoxy-phenethyl)-isoindigo) that were more potent than meisoindigo and comparable to 6-bromoindirubin-3'-oxime on leukemic K562 and liver HuH7 cells were identified. Structure-activity relationships showed the importance of keeping one of the lactam NH in an unsubstituted state. Substitution of the other lactam NH with aryl or arylalkyl side chains retained or improved activity in most instances. An intact exocyclic double bond was also essential, possibly to maintain planarity and rigidity of the isoindigo scaffold. None of the compounds were found to inhibit CDK2 in an in vitro assay, in spite of reports linking the antiproliferative activities of meisoindigo and other isoindigos to CDK2 inhibition. Hence, these functionalized isoindigos disrupted cell growth and proliferation by other mechanistic pathways that did not involve CDK2 inhibition.


Assuntos
Antineoplásicos/síntese química , Indóis/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Simulação por Computador , Quinase 2 Dependente de Ciclina/antagonistas & inibidores , Quinase 2 Dependente de Ciclina/metabolismo , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Indóis/química , Indóis/farmacologia , Células K562 , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/farmacologia , Relação Estrutura-Atividade
7.
FASEB J ; 20(8): 1152-61, 2006 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16770014

RESUMO

Kainate is a glutamate analog that has been widely used in pharmacological studies of neuronal injury related to ischemic conditions and epilepsy. While altered lipid metabolism has been implicated in kainate action, no study has yet investigated the associated changes in lipid metabolites on a systems scale. Here we describe a mass spectrometry-based approach for profiling of lipid mixtures in a nontargeted fashion. Combined with tandem mass spectrometry, this method aims to identify lipids that are altered between two conditions, the kainate-treated and the control hippocampal tissues. In addition to reductions in major phospholipids with mainly polyunsaturated fatty acyl chains, we find elevated levels of ions that correspond to acylated forms of phosphatidylethanolamines and ceramides. Acylated phosphatidylethanolamines are neuroprotective lipids and precursors for anandamide, which signals via cannabinoid receptors. Quantitative analysis of ceramides shows that many molecular species with different acyl compositions are increased during kainate treatment. This increase is mainly restricted to neurons rather than other brain cells in the hippocampus as revealed by immunohistochemistry of brain slices.


Assuntos
Encéfalo/efeitos dos fármacos , Agonistas de Aminoácidos Excitatórios/toxicidade , Ácido Caínico/toxicidade , Metabolismo dos Lipídeos/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Animais , Encéfalo/citologia , Ceramidas/análise , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Lipídeos/química , Neurônios/metabolismo , Fosfatidiletanolaminas/análise , Ratos , Ratos Wistar , Espectrometria de Massas por Ionização por Electrospray , Esfingolipídeos/análise
8.
Am J Pharmacogenomics ; 5(5): 281-92, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-16196498

RESUMO

The ultimate goal of cancer proteomics is to adapt proteomic technologies for routine use in clinical laboratories for the purpose of diagnostic and prognostic classification of disease states, as well as in evaluating drug toxicity and efficacy. Analysis of tumor-specific proteomic profiles may also allow better understanding of tumor development and the identification of novel targets for cancer therapy. The biological variability among patient samples as well as the huge dynamic range of biomarker concentrations are currently the main challenges facing efforts to deduce diagnostic patterns that are unique to specific disease states. While several strategies exist to address this problem, we focus here on cancer classification using mass spectrometry (MS) for proteomic profiling and biomarker identification. Recent advances in MS technology are starting to enable high-throughput profiling of the protein content of complex samples. For cancer classification, the protein samples from cancer patients and noncancer patients or from different cancer stages are analyzed through MS instruments and the MS patterns are used to build a diagnostic classifier. To illustrate the importance of feature selection in cancer classification, we present a method based on support vector machine-recursive feature elimination (SVM-RFE), demonstrated on two cancer datasets from ovarian and lung cancer.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias/classificação , Proteoma/análise , Humanos , Espectrometria de Massas , Neoplasias/diagnóstico , Neoplasias/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA