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1.
J Neurosci ; 33(46): 18175-89, 2013 Nov 13.
Artículo en Inglés | MEDLINE | ID: mdl-24227726

RESUMEN

Intracellular tau aggregates are the neuropathological hallmark of several neurodegenerative diseases, including Alzheimer's disease, progressive supranuclear palsy, and cases of frontotemporal dementia, but the link between these aggregates and neurodegeneration remains unclear. Neuronal models recapitulating the main features of tau pathology are necessary to investigate the molecular mechanisms of tau malfunction, but current models show little and inconsistent spontaneous tau aggregation. We show that dorsal root ganglion (DRG) neurons in transgenic mice expressing human P301S tau (P301S-htau) develop tau pathology similar to that found in brain and spinal cord and a significant reduction in mechanosensation occurs before detectable fibrillar tau formation. DRG neuronal cultures established from adult P301S-htau mice at different ages retained the pattern of aberrant tau found in vivo. Moreover, htau became progressively hyperphosphorylated over 2 months in vitro beginning with nonsymptomatic neurons, while hyperphosphorylated P301S-htau-positive neurons from 5-month-old mice cultured for 2 months died preferentially. P301S-htau-positive neurons grew aberrant axons, including spheroids, typically found in human tauopathies. Neurons cultured at advanced stages of tau pathology showed a 60% decrease in the fraction of moving mitochondria. SEG28019, a novel O-GlcNAcase inhibitor, reduced steady-state pSer396/pSer404 phosphorylation over 7 weeks in a significant proportion of DRG neurons showing for the first time the possible beneficial effect of prolonged dosing of O-GlcNAcase inhibitor in vitro. Our system is unique in that fibrillar tau forms without external manipulation and provides an important new tool for understanding the mechanisms of tau dysfunction and for screening of compounds for treatment of tauopathies.


Asunto(s)
Células Receptoras Sensoriales/metabolismo , Tauopatías/metabolismo , beta-N-Acetilhexosaminidasas/antagonistas & inhibidores , Proteínas tau/biosíntesis , Animales , Células Cultivadas , Evaluación Preclínica de Medicamentos/métodos , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células Receptoras Sensoriales/efectos de los fármacos , Células Receptoras Sensoriales/patología , Tauopatías/tratamiento farmacológico , Tauopatías/genética , Tauopatías/patología , beta-N-Acetilhexosaminidasas/metabolismo , Proteínas tau/genética
2.
J Org Chem ; 78(7): 3208-21, 2013 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-23458237

RESUMEN

A general and efficient method has been developed for the synthesis of sugar-derived azepane nitrones starting from aldohexoses, with an intramolecular condensation of aldehyde and hydroxylamine as the key step. Through this strategy, each aldohexose produced a pair of azepane nitrones, which are precursors of various azepane iminosugars.


Asunto(s)
Carbohidratos/química , Óxidos de Nitrógeno/síntesis química , Estructura Molecular , Óxidos de Nitrógeno/química
3.
J Org Chem ; 78(20): 10298-309, 2013 Oct 18.
Artículo en Inglés | MEDLINE | ID: mdl-24032658

RESUMEN

Pochonicine, the first naturally occurring polyhydroxylated pyrrolizidine containing an acetamidomethyl group, which was isolated from Pochonia suchlasporia var. suchlasporia TAMA 87, together with its enantiomer and their C-1 and/or C-3 epimers, have been synthesized from the sugar-derived cyclic nitrones 9D and 9L, respectively. An in-depth NMR study showed that both the (1)H and (13)C NMR spectra of the synthetic pochonicines (1D and 1L) matched very well with those of natural pochonicine in D2O, which unequivocally determined the relative configuration of the natural product as 1D or 1L. In addition, comparison of the optical rotations of the synthetic pochonicines and that of the natural product, but more convincingly their glycosidase inhibition profiles, confirmed the absolute configuration of natural pochonicine as 1R,3S,5R,6R,7S,7aR. Thereby, the structure of natural pochonicine was unequivocally determined as (+)-(1R,3S,5R,6R,7S,7aR)-pochonicine (1D). Glycosidase inhibition experiments showed that natural pochonicine 1D and its epimers 2D, 3D, and 4D all are powerful inhibitors of hexosaminidases (five ß-N-acetylglucosaminidases and two ß-N-acetylgalactosaminidases) while their enantiomers 1L, 2L, 3L, and 4L are much weaker inhibitors of the same enzymes. (-)-3-epi-Pochonicine (2L) was found to be a potent and selective inhibitor of α-l-rhamnosidase. None of the compounds showed any inhibition of α-GalNAcase.


Asunto(s)
Inhibidores Enzimáticos/síntesis química , Alcaloides de Pirrolicidina/síntesis química , beta-N-Acetilhexosaminidasas/antagonistas & inhibidores , beta-N-Acetilhexosaminidasas/química , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/aislamiento & purificación , Inhibidores Enzimáticos/farmacología , Espectroscopía de Resonancia Magnética , Estructura Molecular , Alcaloides de Pirrolicidina/química , Alcaloides de Pirrolicidina/aislamiento & purificación , Alcaloides de Pirrolicidina/farmacología , Estereoisomerismo
5.
Carbohydr Res ; 339(1): 51-65, 2004 Jan 02.
Artículo en Inglés | MEDLINE | ID: mdl-14659671

RESUMEN

Novel, structurally modified potential mimics of the second messenger D-myo-inositol 1,4,5-trisphosphate, based on the biologically active regioisomer D-myo-inositol 1,4,6-trisphosphate, were synthesised. DL-5-O-Benzyl-1,4,6-tri-O-p-methoxybenzyl-myo-inositol was the key intermediate for the preparation of the following compounds: DL-3-deoxy-, DL-3-deoxy-2-O-methyl-, DL-3-O-(2-hydroxyethyl)-, DL-3-O-(3-hydroxypropyl)- and DL-3-O-(4-hydroxybutyl)-myo-inositol 1,4,6-trisphosphate. DL-1,4,6-Tri-O -allyl-5-O-benzyl-myo-inositol was used to prepare DL-2-O-methyl-myo-inositol 1,4,6-trisphosphate. Deoxy-compounds were prepared by reduction of the corresponding tosylated intermediate using Super Hydride. The hydroxyalkyl groups were introduced at the C-3 of myo-inositol using the corresponding benzyl protected hydroxy alkyl bromide via the cis-2,3-O-dibutylstannylene acetal. Methylation and benzylation at C-2 was accomplished using methyl iodide and benzyl bromide, respectively, in the presence of sodium hydride. Deblocking of p-methoxybenzyl groups was accomplished with TFA in dichloromethane and the allyl groups were removed by isomerisation to the cis-prop-1-enyl derivative, which was hydrolysed under acidic conditions to give the corresponding 1,4,6-triol. The 1,4,6-triols were phosphitylated with the P(III) reagent bis(benzyloxy)(diisopropylamino)phosphine in the presence of 1H-tetrazole then oxidised with 3-chloroperoxybenzoic acid followed by deblocking by hydrogenolysis to give DL-2-O-methyl-, DL-3-O-deoxy-, DL-3-O-deoxy-2-O-methyl-, DL-3-O-(2-hydroxyethyl)-, DL-3-O-(3-hydroxypropyl)- and DL-3-O-(4-hydroxybutyl)-myo-inositol 1,4,6-trisphosphate, respectively.


Asunto(s)
Inositol 1,4,5-Trifosfato/análogos & derivados , Inositol 1,4,5-Trifosfato/síntesis química , Compuestos de Bencilo/química , Hidrocarburos Yodados/química , Hidrogenación , Inositol 1,4,5-Trifosfato/química , Metilación , Conformación Molecular , Oxidación-Reducción , Estereoisomerismo , Ácido Trifluoroacético/química
6.
Drug Discov Today ; 16(3-4): 107-18, 2011 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-20817006

RESUMEN

Iminosugars comprise the most attractive class of carbohydrate mimetics reported to date and are ideally positioned to take advantage of our increasing understanding of glycobiology in the search for new medicines. First-generation iminosugar drugs suffered from lack of adequate selectivity, resulting in considerable side-effects in the clinic. Current efforts directed towards second-generation compounds, encompassing a much greater range of structures and addressing a wider selection of biochemical targets, are enabling the identification and development of suitable candidates that benefit from improved activity and selectivity. Furthermore, second-generation compounds can address a variety of established targets that have previously proved refractory to other compound classes. This review focuses on the breadth of opportunities provided by second-generation leads from iminosugars (Seglins™).


Asunto(s)
Descubrimiento de Drogas/métodos , Descubrimiento de Drogas/tendencias , Iminoazúcares/química , Fenómenos Químicos , Iminoazúcares/síntesis química , Estructura Molecular , Relación Estructura-Actividad
7.
Org Lett ; 13(16): 4414-7, 2011 Aug 19.
Artículo en Inglés | MEDLINE | ID: mdl-21797200

RESUMEN

Total synthesis of the proposed structure of (-)-hyacinthacine C(5) and its epimers at C6 and C7 is described. A key step of the synthesis was the construction of the bicyclic pyrrolizidine system by means of a nucleophilic addition of a dithiane to a cyclic nitrone followed by a Cope-House cyclization.


Asunto(s)
Alcaloides de Pirrolicidina/síntesis química , Ciclización , Hidroxilación , Estructura Molecular
8.
Biochem Biophys Res Commun ; 320(4): 1262-70, 2004 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-15249226

RESUMEN

D-6-Deoxy-myo-inositol 1,3,4,5-tetrakisphosphate [D-6-deoxy-Ins(1,3,4,5)P(4)] 3 is a novel deoxygenated analogue of D-myo-inositol 1,3,4,5-tetrakisphosphate [Ins(1,3,4,5)P(4)] 2, a central and enigmatic molecule in the polyphosphoinositide pathway of cellular signalling. D-6-Deoxy-Ins(1,3,4,5)P(4) is a moderate inhibitor of Ins(1,4,5)P(3) 5-phosphatase [1.8microM] compared to Ins(1,3,4,5)P(4) [0.15microM] and similar to that of L-Ins(1,3,4,5)P(4) [1.8microM]. In displacement of [(3)H] Ins(1,4,5)P(3) from the rat cerebellar Ins(1,4,5)P(3) receptor, while slightly weaker [IC(50)=800nM] than that of D-Ins(1,3,4,5)P(4) [IC(50)=220nM], 3 is less markedly different and again similar to that of L-Ins(1,3,4,5)P(4) [IC(50)=660nM]. 3 is an activator of I(CRAC) when inward currents are measured in RBL-2H3-M1 cells using patch-clamp electrophysiological techniques with a facilitation curve different to that of Ins(1,3,4,5)P(4). Physicochemical properties were studied by potentiometric (31)P and (1)H NMR titrations and were similar to those of Ins(1,3,4,5)P(4) apart from the observation of a biphasic titration curve for the P1 phosphate group. A novel vicinal phosphate charge-induced conformational change of the inositol ring above pH 10 was observed for D-6-deoxy-Ins(1,3,4,5)P(4) that would normally be hindered because of the central stabilising role played by the 6-OH group in Ins(1,3,4,5)P(4). We conclude that the 6-OH group in Ins(1,3,4,5)P(4) is crucial for its physicochemical behaviour and biological properties of this key inositol phosphate.


Asunto(s)
Canales de Calcio/química , Fosfatos de Inositol/química , Monoéster Fosfórico Hidrolasas/química , Receptores Citoplasmáticos y Nucleares/química , Canales de Calcio/metabolismo , Concentración de Iones de Hidrógeno , Receptores de Inositol 1,4,5-Trifosfato , Fosfatos de Inositol/análisis , Fosfatos de Inositol/metabolismo , Inositol Polifosfato 5-Fosfatasas , Conformación Molecular , Monoéster Fosfórico Hidrolasas/metabolismo , Unión Proteica , Receptores Citoplasmáticos y Nucleares/metabolismo , Relación Estructura-Actividad
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