RESUMEN
Both the inhibition of inflammatory flares and the treatment of hyperuricemia itself are included in the management of gout. Extending our efforts to development of gout therapy, two series of benzoxazole deoxybenzoin oxime derivatives as inhibitors of innate immune sensors and xanthine oxidase (XOD) were discovered in improving hyperuricemia and acute gouty arthritis. In vitro studies revealed that most compounds not only suppressed XOD activity, but blocked activations of NOD-like receptor (NLRP3) inflammasome and Toll-like receptor 4 (TLR4) signaling pathway. More importantly, (E)-1-(6-methoxybenzo[d]oxazol-2-yl)-2-(4-methoxyphenyl)ethanone oxime (5d) exhibited anti-hyperuricemic and anti-acute gouty arthritis activities through regulating XOD, NLRP3 and TLR4. Compound 5d may serve as a tool compound for further design of anti-gout drugs targeting both innate immune sensors and XOD.
Asunto(s)
Aminas/farmacología , Inhibidores Enzimáticos/farmacología , Supresores de la Gota/farmacología , Gota/tratamiento farmacológico , Oximas/farmacología , Xantina Oxidasa/antagonistas & inhibidores , Aminas/síntesis química , Aminas/química , Animales , Benzoína/análogos & derivados , Benzoína/química , Benzoína/farmacología , Benzoxazoles/química , Benzoxazoles/farmacología , Línea Celular , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Supresores de la Gota/síntesis química , Supresores de la Gota/química , Células HEK293 , Humanos , Inmunidad Innata/efectos de los fármacos , Hígado/enzimología , Masculino , Ratones , Ratones Endogámicos , Estructura Molecular , Oximas/síntesis química , Oximas/química , Ratas , Ratas Sprague-Dawley , Relación Estructura-Actividad , Ácido Úrico/sangre , Xantina Oxidasa/metabolismoRESUMEN
Eight new C-4-alkylated deoxybenzoins (1-8), three new diphenylethylenes (9-11), and five known diphenylethylenes were isolated from Arundina graminifolia. The structures of 1-11 were elucidated by spectroscopic methods including extensive 1D and 2D NMR techniques. Compounds 9-11 are the first naturally occurring diphenylethylenes possessing a hydroxyethyl unit. Compounds 1-11 were evaluated for cytotoxicity against five human tumor cell lines. Compounds 4, 5, and 9-11 showed significant cytotoxicity against five cancer cell lines, with IC50 values ranging from 1.8 to 8.7 µM.
Asunto(s)
Antineoplásicos Fitogénicos/aislamiento & purificación , Antineoplásicos Fitogénicos/farmacología , Benzoína/análogos & derivados , Medicamentos Herbarios Chinos/aislamiento & purificación , Medicamentos Herbarios Chinos/farmacología , Etilenodiaminas/aislamiento & purificación , Etilenodiaminas/farmacología , Orchidaceae/química , Antineoplásicos Fitogénicos/química , Benzoína/química , Benzoína/aislamiento & purificación , Benzoína/farmacología , Ensayos de Selección de Medicamentos Antitumorales , Medicamentos Herbarios Chinos/química , Etilenodiaminas/química , Humanos , Concentración 50 Inhibidora , Estructura Molecular , Resonancia Magnética Nuclear Biomolecular , Estilbenos/químicaRESUMEN
BACKGROUND AND PURPOSE: The melastatin-related transient receptor potential TRPM3 is a calcium-permeable nonselective cation channel that can be activated by the neurosteroid pregnenolone sulphate (PregS) and heat. TRPM3-deficient mice show an impaired perception of noxious heat. Hence, drugs inhibiting TRPM3 possibly get in focus of analgesic therapy. EXPERIMENTAL APPROACH: Fluorometric methods were used to identify novel TRPM3-blocking compounds and to characterize their potency and selectivity to block TRPM3 but not other sensory TRP channels. Biophysical properties of the block were assessed using electrophysiological methods. Single cell calcium measurements confirmed the block of endogenously expressed TRPM3 channels in rat and mouse dorsal root ganglion (DRG) neurones. KEY RESULTS: By screening a compound library, we identified three natural compounds as potent blockers of TRPM3. Naringenin and hesperetin belong to the citrus fruit flavanones, and ononetin is a deoxybenzoin. Eriodictyol, a metabolite of naringenin and hesperetin, was still biologically active as a TRPM3 blocker. The compounds exhibited a marked specificity for recombinant TRPM3 and blocked PregS-induced [Ca(2+)]i signals in freshly isolated DRG neurones. CONCLUSION AND IMPLICATIONS: The data indicate that citrus fruit flavonoids are potent and selective blockers of TRPM3. Their potencies ranged from upper nanomolar to lower micromolar concentrations. Since physiological functions of TRPM3 channels are still poorly defined, the development and validation of potent and selective blockers is expected to contribute to clarifying the role of TRPM3 in vivo. Considering the involvement of TRPM3 in nociception, TRPM3 blockers may represent a novel concept for analgesic treatment.
Asunto(s)
Benzoína/análogos & derivados , Bloqueadores de los Canales de Calcio/aislamiento & purificación , Citrus/química , Fabaceae/química , Flavanonas/aislamiento & purificación , Ganglios Espinales/metabolismo , Canales Catiónicos TRPM/antagonistas & inhibidores , Animales , Benzoína/aislamiento & purificación , Benzoína/farmacología , Calcio/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Señalización del Calcio/efectos de los fármacos , Evaluación Preclínica de Medicamentos , Fabaceae/metabolismo , Flavanonas/farmacología , Células HEK293 , Hesperidina/aislamiento & purificación , Hesperidina/farmacología , Humanos , Potenciales de la Membrana , Ratones , Ratones Endogámicos C57BL , Pregnenolona/farmacología , Ratas , Ratas Wistar , Metabolismo Secundario , Canales Catiónicos TRPM/genética , Canales Catiónicos TRPM/metabolismoRESUMEN
Prenyl-phloroglucinol derivatives from hop plants have been shown to have anticancer activities. This study is the first to investigate the anticancer effects of the new phloroglucinol derivative (2,4-bis(4-fluorophenylacetyl)phloroglucinol; BFP). BFP induced cell death and anti-proliferation in three glioma, U251, U87 and C6 cells, but not in primary human astrocytes. BFP-induced concentration-dependently cell death in glioma cells was determined by MTT and SRB assay. Moreover, BFP-induced apoptotic cell death in glioma cells was measured by Hochest 33258 staining and fluorescence-activated cell sorter (FACS) of propidine iodine (PI) analysis. Treatment of U251 human glioma cells with BFP was also found to induce reactive oxygen species (ROS) generation, which was detected by a fluorescence dye used FACS analysis. Treatment of BFP also increased a number of signature endoplasmic reticulum (ER) stress markers glucose-regulated protein (GRP)-78, GRP-94, IRE1, phosphorylation of eukaryotic initiation factor-2α (eIF-2α) and up-regulation of CAAT/enhancer-binding protein homologous protein (CHOP). Moreover, treatment of BFP also increased the down-stream caspase activation, such as pro-caspase-7 and pro-caspase-12 degradation, suggesting the induction of ER stress. Furthermore, BFP also induced caspase-9 and caspase-3 activation as well as up-regulation of cleaved PARP expression. Treatment of antioxidants, or pre-transfection of cells with GRP78 or CHOP siRNA reduced BFP-mediated apoptotic-related protein expression. Taken together, the present study provides evidences to support that ROS generation, GRP78 and CHOP activation are mediating the BFP-induced human glioma cell apoptosis.
Asunto(s)
Antineoplásicos Fitogénicos/uso terapéutico , Apoptosis/efectos de los fármacos , Benzoína/análogos & derivados , Estrés del Retículo Endoplásmico/efectos de los fármacos , Glioma/tratamiento farmacológico , Humulus/química , Floroglucinol/análogos & derivados , Floroglucinol/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Antineoplásicos Fitogénicos/farmacología , Benzoína/aislamiento & purificación , Benzoína/farmacología , Benzoína/uso terapéutico , Biomarcadores/metabolismo , Caspasas/metabolismo , Línea Celular Tumoral , Relación Dosis-Respuesta a Droga , Chaperón BiP del Retículo Endoplásmico , Glioma/metabolismo , Proteínas de Choque Térmico/metabolismo , Humanos , Floroglucinol/aislamiento & purificación , Floroglucinol/farmacología , Fitoterapia , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Factor de Transcripción CHOP/metabolismoRESUMEN
BACKGROUND: Litchi chinensis is regarded as one of the 'heating' fruits in China, which causes serious inflammation symptoms to people. METHODS: In the current study, the effects of isolates of litchi on prostaglandin E(2) (PGE(2)) and nitric oxide (NO) production in J774 murine macrophage cells were investigated. RESULTS: The AcOEt extract (EAE) of litchi was found effective on stimulating PGE(2) production, and three compounds, benzyl alcohol, hydrobenzoin and 5-hydroxymethyl-2-furfurolaldehyde (5-HMF), were isolated and identified from the EAE. Benzyl alcohol caused markedly increase in PGE(2) and NO production, compared with lipopolysaccharide (LPS) as positive control, and in a dose-dependent manner. Hydrobenzoin and 5-HMF were found in litchi for the first time, and both of them stimulated PGE(2) and NO production moderately in a dose-dependent manner. Besides, regulation of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) mRNA expression and NF-κB (p50) activation might be involved in mechanism of the stimulative process. CONCLUSION: The study showed, some short molecular compounds in litchi play inflammatory effects on human.
Asunto(s)
Dinoprostona/biosíntesis , Inflamación/inducido químicamente , Litchi/efectos adversos , Macrófagos/efectos de los fármacos , Óxido Nítrico/biosíntesis , Extractos Vegetales/efectos adversos , Animales , Benzoína/efectos adversos , Benzoína/análogos & derivados , Benzoína/aislamiento & purificación , Alcohol Bencilo/efectos adversos , Alcohol Bencilo/aislamiento & purificación , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Relación Dosis-Respuesta a Droga , Frutas , Furanos/efectos adversos , Furanos/aislamiento & purificación , Inflamación/metabolismo , Lipopolisacáridos , Litchi/química , Macrófagos/metabolismo , Ratones , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/genética , Óxido Nítrico Sintasa de Tipo II/metabolismo , Extractos Vegetales/química , ARN Mensajero/metabolismoRESUMEN
A new solid phase extraction method for separation and preconcentration of trace amounts of uranium, thorium, and zirconium in water samples is proposed. The procedure is based on the adsorption of U(VI), Th(IV) and Zr(IV) ions on a column of Amberlite XAD-2000 resin loaded with alpha-benzoin oxime prior to their simultaneous spectrophotometric determination with Arsenazo III using orthogonal signal correction partial least squares method. The enrichment factor for preconcentration of uranium, thorium, and zirconium was found to be 100. The detection limits for U(VI), Th(IV) and Zr(IV) were 0.50, 0.54, and 0.48microgL(-1), respectively. The precision of the method, evaluated as the relative standard deviation obtained by analyzing a series of 10 replicates, was below 4% for all elements. The practical applicability of the developed sorbent was examined using synthetic seawater, natural waters and ceramic samples.
Asunto(s)
Métodos Analíticos de la Preparación de la Muestra/métodos , Benzoína/análogos & derivados , Contaminantes Ambientales/análisis , Contaminantes Ambientales/aislamiento & purificación , Metales Pesados/análisis , Metales Pesados/aislamiento & purificación , Oximas/química , Resinas Sintéticas/química , Extracción en Fase Sólida/métodos , Adsorción , Benzoína/química , Calibración , Compuestos Cromogénicos/química , Contaminantes Ambientales/química , Concentración de Iones de Hidrógeno , Análisis de los Mínimos Cuadrados , Límite de Detección , Metales Pesados/química , Análisis Multivariante , Procesamiento de Señales Asistido por Computador , Espectrofotometría , Torio/análisis , Torio/química , Torio/aislamiento & purificación , Factores de Tiempo , Uranio/análisis , Uranio/química , Uranio/aislamiento & purificación , Circonio/análisis , Circonio/química , Circonio/aislamiento & purificaciónRESUMEN
Furoin, a benzoin analogue, was examined as novel fluorogenic reagent for the selective and sensitive LC determination of various guanidines after pre-column derivatization. The derivatization reaction was carried out at 100 degrees C for 5 min to give adducts that were separated on a Phenomenex Synergi MAX-RP column and detected at lambda(em)=410 nm with lambda(ex)=325 nm. The reagent showed to be useful both for determining together arginine (Arg) and creatine (CT) in dietary supplements under elution isocratic conditions and for the simultaneous analysis of a variety of guanidines in biological samples (human plasma and urine) under elution gradient conditions. The detection limits ranged from 7 to 25 fmol. Recovery studies showed good results for all determined guanidino compounds (85.6-106.2%; R.S.D.=1.1-6.2%).
Asunto(s)
Benzoína/análogos & derivados , Benzoína/química , Cromatografía Liquida/métodos , Guanidinas/análisis , Indicadores y Reactivos/química , Calibración , Suplementos Dietéticos/análisis , Furanos , Guanidinas/sangre , Guanidinas/orina , Humanos , Estructura Molecular , Estándares de Referencia , Sensibilidad y Especificidad , Factores de TiempoRESUMEN
Deoxybenzoins are plant compounds with similar structure to isoflavones. In this study, we evaluated the ability of two synthesized deoxybenzoins (compound 1 and compound 2) (a) to influence the activity of the estrogen receptor subtypes ERalpha and ERbeta in HeLa cells co-transfected with an estrogen response element-driven luciferase reporter gene and ERalpha- or ERbeta-expression vectors, (b) to modulate the IGFBP-3 and pS2 protein in MCF-7 breast cancer cells, (c) to induce mineralization of KS483 osteoblasts and (d) to affect the cell viability of endometrial (Ishikawa) and breast (MCF-7, MDA-MB-231) cancer cells. Docking and binding energy calculations were performed using the mixed Monte Carlo/Low Mode search method (Macromodel 6.5). Compound 1 displayed significant estrogenic activity via ERbeta but no activity via ERalpha. Compound 2 was an estrogen-agonist via ERalpha and antagonist via ERbeta. Both compounds increased, like the pure antiestrogen ICI182780, the IGFBP-3 levels. Compound 2 induced, like 17beta-estradiol, significant mineralization in osteoblasts. The cell viability of Ishikawa cells was unchanged in the presence of either compound. Compound 1 increased MCF-7 cell viability consistently with an increase in pS2 levels, whereas compound 2 inhibited the cell viability. Molecular modeling confirmed the agonistic or antagonistic behaviour of compound 2 via ER subtypes. Compound 2, being an agonist in osteoblasts, an antagonist in breast cancer cells, with no estrogenic effects in endometrial cancer cells, makes it a potential selective estrogen receptor modulator and a choice for hormone replacement therapy.
Asunto(s)
Benzoína/análogos & derivados , Calcificación Fisiológica/efectos de los fármacos , Receptor alfa de Estrógeno/metabolismo , Receptor beta de Estrógeno/metabolismo , Estrógenos/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Benzoína/síntesis química , Benzoína/química , Benzoína/metabolismo , Benzoína/farmacología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Estradiol/farmacología , Antagonistas de Estrógenos/química , Antagonistas de Estrógenos/metabolismo , Antagonistas de Estrógenos/farmacología , Estrógenos/agonistas , Femenino , Inhibidores de Crecimiento/metabolismo , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Método de Montecarlo , Osteoblastos/metabolismo , Fitoestrógenos/metabolismo , Fitoestrógenos/farmacología , Moduladores Selectivos de los Receptores de Estrógeno/química , Moduladores Selectivos de los Receptores de Estrógeno/metabolismo , Factor Trefoil-1 , Proteínas Supresoras de Tumor/metabolismoRESUMEN
Although deoxybenzoins are intermediates in the synthesis of isoflavones, their estrogenic activity has not been investigated. Eleven deoxybenzoins were synthesized and their estrogenicity was evaluated. While their affinities for estrogen receptors (ER) ERalpha and ERbeta were found grossly comparable to those of daidzein, some exhibited considerable selectivity and transcriptional bias toward ERbeta, which appeared to allow for enhancement of ER-mediated transcription via deoxybenzoin binding of ERbeta. Their activity to stimulate the proliferation of ER-positive breast cancer cells and regulate the expression of endogenous and stably transfected reporter genes differed considerably, with some inhibiting cell proliferation while effectively inducing gene expression at the same time. Molecular modeling confirmed that deoxybenzoins fit well in the ligand binding pocket of ERbeta, albeit with different orientations. Our data support the view that deoxybenzoins constitute a promising new class of ERbeta-biased phytoestrogens.
Asunto(s)
Benzoína/análogos & derivados , Benzoína/química , Benzoína/farmacología , Isoflavonas/clasificación , Isoflavonas/farmacología , Preparaciones de Plantas/clasificación , Preparaciones de Plantas/farmacología , Receptores de Estrógenos/metabolismo , Fosfatasa Alcalina/metabolismo , Benzoína/síntesis química , División Celular/efectos de los fármacos , Línea Celular , Activación Enzimática/efectos de los fármacos , Estradiol/farmacología , Receptor alfa de Estrógeno , Receptor beta de Estrógeno , Genes Reporteros/genética , Humanos , Isoflavonas/síntesis química , Isoflavonas/química , Modelos Moleculares , Conformación Molecular , Estructura Molecular , Fitoestrógenos , Preparaciones de Plantas/síntesis química , Preparaciones de Plantas/química , Receptores de Estrógenos/química , Relación Estructura-Actividad , Transcripción Genética/efectos de los fármacosRESUMEN
Aryl metabolites are known to have an important role in the ligninolytic system of white rot fungi. The addition of known precursors and aromatic acids representing lignin degradation products stimulated the production of aryl metabolites (veratryl alcohol, veratraldehyde, p-anisaldehyde, and 3-chloro-p-anisaldehyde) in the white rot fungus Bjerkandera sp. strain BOS55. The presence of manganese (Mn) is known to inhibit the biosynthesis of veratryl alcohol (T. Mester, E. de Jong, and J.A. Field, Appl. Environ. Microbiol. 61:1881-1887, 1995). A new finding of this study was that the production of the other aryl metabolites, p-anisaldehyde and 3-chloro-p-anisaldehyde, was also inhibited by Mn. We attempted to bypass the Mn-inhibited step in the biosynthesis of aryl metabolites by the addition of known and suspected precursors. Most of these compounds were not able to bypass the inhibiting effect of Mn. Only the fully methylated precursors (veratrate, p-anisate, and 3-chloro-p-anisate) provided similar concentrations of aryl metabolites in the presence and absence of Mn, indicating that Mn does not influence the reduction of the benzylic acid group. The addition of deuterated benzoate and 4-hydroxybenzoate resulted in the formation of deuterated aryl metabolites, indicating that these aromatic acids entered into the biosynthetic pathway and were common intermediates to all aryl metabolites. Only deuterated chlorinated anisyl metabolites were produced when the cultures were supplemented with deuterated 3-chloro-4-hydroxybenzoate. This observation combined with the fact that 3-chloro-4-hydroxybenzoate is a natural product of Bjerkandera spp. (H. J. Swarts, F. J. M. Verhagen, J. A. Field, and J. B. P. A. Wijnberg, Phytochemistry 42:1699-1701, 1996) suggest that it is a possible intermediate in chlorinated anisyl metabolite biosynthesis.