RESUMO
Ligand-receptor interactions can be implicated in many pathological events such as chronic neurodegenerative diseases. Thus, the discovery of molecules disrupting this type of interactions could be an interesting therapeutic approach. Polyphenols are well known for their affinity for proteins and several studies have characterized these direct interactions. But studying the direct influence of multi-therapeutic drugs on a ligand-receptor complex relevant to a neurodegenerative disorder is a challenging issue. Solution NMR, molecular modeling and iterative calculations were used to obtain information about the interaction between a phenolic compound, α-glucogallin (α-2) and a ligand/fragment receptor complex neurotensin (NT) and its receptor NTS1. The α-2 was shown to bind to NT and a peptidic fragment of its NTS1 receptor, independently. Although the formation of the corresponding ligand-receptor complex did not seem to be affected, this experimental modeling protocol will enable the evaluation of other anti-amyloidogenic compounds such as blockers of NT-NTS1 binding. These types of studies help in understanding the specificity and influence in binding and can provide information to develop new molecules with a putative pharmacological interest.Communicated by Ramaswamy H. Sarma.
Assuntos
Neurotensina , Receptores de Neurotensina , Ligantes , Modelos Moleculares , Neurotensina/química , Polifenóis , Receptores de Neurotensina/químicaRESUMO
The screening of natural products in the search for new lead compounds against Alzheimer's disease has unveiled several plant polyphenols that are capable of inhibiting the formation of toxic ß-amyloid fibrils. Gallic acid based gallotannins are among these polyphenols, but their antifibrillogenic activity has thus far been examined using "tannic acid", a commercial mixture of gallotannins and other galloylated glucopyranoses. The first total syntheses of two true gallotannins, a hexagalloylglucopyranose and a decagalloylated compound whose structure is commonly used to depict "tannic acid", are now described. These depsidic gallotannins and simpler galloylated glucose derivatives all inhibit amyloid ß-peptide (Aß) aggregation inâ vitro, and monogalloylated α-glucogallin and a natural ß-hexagalloylglucose are shown to be the strongest inhibitors.
Assuntos
Doença de Alzheimer/genética , Peptídeos beta-Amiloides/química , Ácido Gálico/química , Taninos/química , Estrutura Molecular , PolifenóisRESUMO
Dimeric stilbene glucosides 1-3 [two diastereomers of (-)-gnemonoside A (1a and 1b), (-)-gnemonoside C (2), and (-)-gnemonoside D (3)] as well as a mixture of the two enantiomers of gnetin C (4) were isolated from the rhizomes of Gnetum africanum. The two enantiomers of gnetin C, (+)-4 and (-)-4, were obtained from the aglycones of 1a and 1b, respectively. The configurations of these stilbenoids were investigated by NMR and vibrational circular dichroism (VCD) experiments. The absolute configurations of (-)-1a, (-)-2, (-)-3, and (-)-4 were established as 7aS,8aS by VCD spectroscopy in combination with density functional theory calculations. The antiamyloidogenic activity of the isolated stilbenes was also evaluated versus beta-amyloid fibrils. The four glucosides of gnetin C (1a, 1b, 2, and 3) were found to be the most active compounds, with inhibition percentages of 56, 56, 58, and 54 at 10 µM, respectively.
Assuntos
Glucosídeos/química , Gnetum/química , Fármacos Neuroprotetores/isolamento & purificação , Estilbenos/química , Benzofuranos/química , Benzofuranos/isolamento & purificação , Camarões , Dicroísmo Circular , Glucosídeos/isolamento & purificação , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Ressonância Magnética Nuclear Biomolecular , Rizoma/química , Estereoisomerismo , Estilbenos/isolamento & purificaçãoRESUMO
Stilbenes have received much attention during the last two decades following the discovery of resveratrol in wine. Since then, there have been a growing number of papers reporting various biological activities of naturally occurring stilbenes. The aim of this study was to determine new minor stilbenes from Vitis vinifera stalks. Purification of these compounds was achieved by means of centrifugal partition chromatography, a versatile separation technique that does not require a solid stationary phase. Viniphenol A (1), a new resveratrol hexamer, was isolated along with five oligostilbenoids identified in V. vinifera for the first time, ampelopsin C, davidiol A, leachianol F, leachianol G, and E-maackin, a dimer with an unusual dioxane moiety, and 14 known hydroxystilbenes. The structure and stereochemistry of viniphenol A were determined on the basis of spectroscopic data analysis and molecular modeling under NMR constraints. Viniphenol A showed protective effects against amyloid-ß-induced toxicity in PC12 cell cultures.
Assuntos
Estilbenos/isolamento & purificação , Estilbenos/farmacologia , Vitis/química , Peptídeos beta-Amiloides/farmacologia , Animais , Antioxidantes/farmacologia , Catequina/farmacologia , Dioxanos/química , Estrutura Molecular , Ressonância Magnética Nuclear Biomolecular , Células PC12 , Ratos , Resveratrol , Estilbenos/químicaRESUMO
BACKGROUND: Viticultural residues from commercial viticultural activities represent a potentially important source of bioactive stilbenes such as resveratrol. The main aim of the present study was therefore to isolate, identify and perform biological assays against amyloid-ß peptide aggregation of original stilbenes from Vitis vinifera shoots. RESULTS: A new resveratrol oligomer, (Z)-cis-miyabenol C (3), was isolated from Vitis vinifera grapevine shoots together with two newly reported oligostilbenes from Vitis vinifera shoots, vitisinol C (1) and (E)-cis-miyabenol C (2), and six known compounds: piceatannol, resveratrol, (E)-ε-viniferin (trans-ε-viniferin), ω-viniferin, vitisinol C and (E)-miyabenol C. The structures of these resveratrol derivatives were established on the basis of detailed spectroscopic analysis including nuclear magnetic resonance experiments. All the newly reported compounds were tested for their anti-aggregative activity against amyloid-ß fibril formation. Vitisinol C was found to exert a significant activity against amyloid-ß aggregation. CONCLUSION: Vitis vinifera grapevine shoots are potentially interesting as a source of new bioactive stilbenes, such as vitisinol C.
Assuntos
Descoberta de Drogas , Resíduos Industriais/análise , Nootrópicos/isolamento & purificação , Extratos Vegetais/química , Brotos de Planta/química , Estilbenos/isolamento & purificação , Vitis/química , Agricultura/economia , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Benzofuranos/análise , Benzofuranos/química , Benzofuranos/economia , Benzofuranos/isolamento & purificação , Cromatografia Líquida de Alta Pressão , França , Humanos , Resíduos Industriais/economia , Estrutura Molecular , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/economia , Fármacos Neuroprotetores/isolamento & purificação , Fármacos Neuroprotetores/farmacologia , Nootrópicos/química , Nootrópicos/economia , Nootrópicos/farmacologia , Fragmentos de Peptídeos/antagonistas & inibidores , Fragmentos de Peptídeos/metabolismo , Fenóis/química , Fenóis/economia , Extratos Vegetais/economia , Agregados Proteicos/efeitos dos fármacos , Agregação Patológica de Proteínas , Espectrometria de Massas por Ionização por Electrospray , Estereoisomerismo , Estilbenos/análise , Estilbenos/química , Estilbenos/economia , Estilbenos/farmacologia , EstilbestroisRESUMO
INTRODUCTION: Grapes are one of the most important fruit crops in the world. The quality of red grape berries greatly depends on skin colour, mainly due to the anthocyanin profile. Today, the American Vitis species have the greatest potential for breeding work. They have multiple resistance properties in comparison with Vitis vinifera but little is known about their anthocyanin content. OBJECTIVE: To determine the anti-oxidant properties and anthocyanin profile of two American species, Vitis candicans and Vitis doaniana, by using LC-MS(n) and LC-NMR. METHODS: Grape extracts were prepared by extraction of berry skins with acidified methanol. The complete structure elucidation of the individual anthocyanins was performed with LC-MS(n) , LC-NMR and NMR experiments. Individual anthocyanins in the extracts were quantified by using malvidin glucoside as external standard. The anti-oxidant activities of grape skin extracts were evaluated by using 1,1-diphenyl-2-picrylhydrazyl (DPPHâ¢) radical scavenging and oxygen radical absorbance capacity (ORAC) assays. RESULTS: By using LC-MS(n) and LC-NMR experiments, 30 anthocyanins were identified and quantified in the two Vitis species, including two new cis-p-coumaroyl derivatives. Vitis candicans and V. doaniana showed significant differences in their anthocyanin profile. These two Vitis species possess low-to-medium anti-oxidant activities in comparison with V. vinifera. CONCLUSION: The profiles of 30 anthocyanins were established unambiguously in two American Vitis species.
Assuntos
Antocianinas/análise , Antioxidantes/análise , Vitis/química , Antocianinas/farmacologia , Antioxidantes/farmacologia , Cromatografia Líquida de Alta Pressão , Sequestradores de Radicais Livres/análise , Sequestradores de Radicais Livres/farmacologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Especificidade da Espécie , Vitis/classificaçãoRESUMO
Flavours extracted from oak wood during barrel ageing contribute to the organoleptic character of wines and spirits. The aim of this work was to identify the glycosidic precursors of the key volatile compounds responsible for oak wood aroma. Oak extract is a very complex matrix and, furthermore, precursors are present in very small quantities. Preparative centrifugal partition chromatography (CPC) is a promising solution for purifying the oak extract. The solvent system was selected on the basis of the partition coefficient of glycosidase enzyme activity (Kca). Thanks to the efficacy of CPC separation, three glucoside gallates were subsequently isolated by HPLC chromatography. Vanillin-(6'-O-galloyl)-O-ß-D-glucopyranoside, 3,4,5-trimethoxyphenyl-(6'-O-galloyl)-O-ß-D-glucopyranoside, and (6R,9R)-3-oxo-α-ionol-9-O-(6'-O-galloyl)-ß-glucopyranoside (macarangioside E) were isolated and identified. This was the first time that vanillin-(6'-O-galloyl)-O-ß-D-glucopyranoside was identified and the first time that macarangioside E was isolated from oak wood. Heating macarangioside E resulted in the formation of megastigmatrienone, which has an aroma reminiscent of tobacco.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Glicosídeos/isolamento & purificação , Quercus/química , Compostos Orgânicos Voláteis/isolamento & purificação , Madeira/química , Aromatizantes/análise , Aromatizantes/isolamento & purificação , Glicosídeos/análise , Compostos Orgânicos Voláteis/análiseRESUMO
BACKGROUND: Alzheimer's disease (AD) is a progressive neurodegenerative disorder. There is a consensus that Aß is a pathologic agent and that its toxic effects, which are at present incompletely understood, may occur through several potential mechanisms. Polyphenols are known to have wide-ranging properties with regard to health and for helping to prevent various diseases like neurodegenerative disorders. Thus inhibiting the formation of toxic Aß assemblies is a reasonable hypothesis to prevent and perhaps treat AD METHODS: Solution NMR and molecular modeling were used to obtain more information about the interaction between the Aß1-40 and the polyphenol ε-viniferin glucoside (EVG) and particularly the Aß residues involved in the complex. RESULTS: The study demonstrates the formation of a complex between two EVG molecules and Aß1-40 in peptide characteristic regions that could be in agreement with the inhibition of aggregation. Indeed, in previous studies, we reported that EVG strongly inhibited in vitro the fibril formation of the full length peptides Aß1-40 and Aß1-42, and had a strong protective effect against PC12 cell death induced by these peptides. CONCLUSION: For the full length peptide Aß1-40, the binding sites observed could explain the EVG inhibitory effect on fibrillization and thus prevent amyloidogenic neurotoxicity. GENERAL SIGNIFICANCE: Even though this interaction might be important at the biological level to explain the protective effect of polyphenols in neurodegenerative diseases, caution is required when extrapolating this in vitro model to human physiology.
Assuntos
Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/química , Benzofuranos/química , Glucosídeos/química , Fragmentos de Peptídeos/química , Polifenóis/química , Estilbenos/química , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/metabolismo , Animais , Benzofuranos/metabolismo , Sítios de Ligação , Linhagem Celular Tumoral , Glucosídeos/metabolismo , Espectroscopia de Ressonância Magnética/métodos , Modelos Moleculares , Células PC12 , Fragmentos de Peptídeos/metabolismo , Polifenóis/metabolismo , Conformação Proteica , Ratos , Estilbenos/metabolismoRESUMO
Wine is a major dietary source of numerous potentially health promoting stilbenoids that have been the subject of many qualitative and quantitative studies. However, our initial HPLC-MS analyses of crude wine samples demonstrated the presence of compounds with molecular weights matching characteristic stilbenoid dimers, trimers, and tetramers that were unaccounted for in the literature. Due to the likelihood that these are known compounds, a chemical dereplication method is highly desirable. We developed such a method using LC-DAD-MS monitored fractionation steps, using adsorption and centrifugal partition chromatography (CPC), to obtain fractions rich in stilbenoids for analysis in stopped-flow LC-NMR. (1)H NMR spectra and MS data were cross-referenced with our laboratory database and the literature for identification. This method yielded highly useful structural information, allowing the characterization of previously unidentified stilbenoids in wine, ampelopsin C, isohopeaphenol, quadrangularin A, and E-ω-viniferin. These results demonstrate the usefulness of stop-flow LC-NMR in conjunction with LC-MS guided fractionation for the dereplication of compounds of interest in general, and specifically for expanding the current knowledge of wine chemistry.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Espectroscopia de Ressonância Magnética/métodos , Estilbenos/análise , Vinho/análise , Espectrometria de MassasRESUMO
Neurotensin (NT) is a tridecapeptide, hormone in the periphery and neurotransmitter in the brain. We used high-resolution nuclear magnetic resonance (NMR) to resolve the three-dimensional structure of NT in a small unilamellar vesicle (SUV) environment. We demonstrate that if the dynamic of the association-dissociation processes of peptide to SUV binding is rapid enough, structural determination can be obtained by solution NMR experiments. Thus, according to the global dynamic of the system, SUVs seem to be an effective model to mimic biological membranes, especially since the lipid composition can be modified or sterols may be added to closely mimic the biological membranes studied. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:2.
Assuntos
Neurotensina/química , Ressonância Magnética Nuclear Biomolecular , Receptores de Neurotensina/química , Lipossomas Unilamelares/química , Modelos Moleculares , Conformação Proteica , Receptores de Neurotensina/metabolismo , SoluçõesRESUMO
Neurotensin (NT) is a tridecapeptide hormone in the periphery and neurotransmitter in the brain that principally activates three receptor subtypes, named NTS1, NTS2, and NTS3. Since little is known about its structure in the presence of its principal receptor NTS1, we determined it using the key domain of the receptor, i.e. the third extracellular loop. We conclude the following: (i) for the receptor fragment, NT binding modifies its central part, underlying the great flexibility and adaptability of this region; (ii) for bound NT, the extended conformation of its C-terminus is confirmed for the first time in experimental conditions and in the presence of a part of the receptor; and (iii) despite some substitutions, the human receptor residues that are involved in the interaction with NT could be similar to those of the rat receptor which play an important role in NT binding.
Assuntos
Neurotensina/química , Fragmentos de Peptídeos/química , Estrutura Terciária de Proteína , Receptores de Neurotensina/química , Sequência de Aminoácidos , Sítios de Ligação , Humanos , Espectroscopia de Ressonância Magnética , Modelos Moleculares , Dados de Sequência Molecular , Neurotensina/metabolismo , Fragmentos de Peptídeos/metabolismo , Ligação Proteica , Conformação Proteica , Isoformas de Proteínas/química , Isoformas de Proteínas/metabolismo , Receptores de Neurotensina/metabolismoRESUMO
The complex etiology of Alzheimer's disease prompts scientists to develop multi-target strategies to combat causes and symptoms. In line with this modern paradigm and as a follow-up to our previous studies, we designed and synthesized a focused collection of new 2-arylbenzofurans and evaluated their biological properties towards specific targets involved in AD, namely human AChE and human BuChE, and Aß fibril formation. Selected compounds were also tested for their ability to inhibit Aß neurotoxicity in terms of neuronal viability loss, and to prevent Aß peptide-binding to cell membrane and intracellular reactive oxygen species (ROS) formation. The different modifications introduced in the structure of our lead compound led to an increase in activity towards one or more of the selected targets: the anticholinesterase activity of some compounds was found to be significantly higher than previously obtained related molecules, and the compounds also proved to possess Aß anti-aggregating properties and neuroprotective effects. The most interesting multi-target compounds were 18, and 1. Interestingly, 1 also showed good selectivity and moderate affinity for CB1 receptor, opening new perspectives in the field of research on AD, since cannabinoid ligands have been widely reported to have neuroprotective properties.
Assuntos
Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Benzofuranos/farmacologia , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/farmacologia , Benzofuranos/síntese química , Benzofuranos/química , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Relação Estrutura-AtividadeRESUMO
Stilbenes are a family of bioactive compounds found in plants. However, only a few stilbenes are present in the human diet. Grape and wine are the main dietary source of stilbenes, resveratrol and piceid being the most common ones. Ultraviolet C light (UVC) postharvest treatment was used to obtain significantly increased stilbene concentration in grapes. A new, previously undescribed-in-grapes stilbene was found after UVC treatment. The process followed to isolate and identify this unknown stilbene is described in the present work. This isolation involved several fractionation steps including counter current chromatography and semi-preparative HPLC due to its low concentration and the presence of structurally related compounds. The structure of the compound was unequivocally identified by NMR spectroscopy analyses including (1)H-NMR; COSY; ROESY; HSQC and HMBC. The compound was identified as isorhapontigenin (ISOR), a stilbene found in traditional Asian medicinal plants. To the best of our knowledge this is the first report of its occurrence in grapes.
Assuntos
Extratos Vegetais/química , Estilbenos/química , Vitis/química , Cromatografia Líquida de Alta Pressão , Estrutura Molecular , Extratos Vegetais/isolamento & purificação , Estilbenos/isolamento & purificação , Raios Ultravioleta , Vitis/efeitos da radiaçãoRESUMO
There are numerous studies indicating that a moderate consumption of red wine provides certain health benefits, such as the protection against neurodegenerative diseases. This protective effect is most likely due to the presence of phenolic compounds in wine. Wine polyphenolic compounds are well known for the antioxidant properties. Oxidative stress is involved in many forms of cellular and molecular deterioration. This damage can lead to cell death and various neurodegenerative disorders, such as Parkinson's or Alzheimer's diseases. Extensive investigations have been undertaken to determine the neuroprotective effects of wine-related polyphenols. In this review we present the neuroprotective abilities of the major classes of wine-related polyphenols.
Assuntos
Citoproteção/efeitos dos fármacos , Neurônios/citologia , Fármacos Neuroprotetores/farmacologia , Polifenóis/farmacologia , Vinho , Animais , Humanos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/química , Oxirredução/efeitos dos fármacos , Polifenóis/químicaRESUMO
The composition and concentration of anthocyanins of grape berry skins were analyzed in order to assess phenotypic variation between four grape wine varieties belonging to 4 different species: Vitis vinifera, Vitis amurensis, Vitis cinerea and Vitis X champinii. High-performance liquid chromatography coupled to mass spectrometry (LC-MS) and NMR spectroscopy (LC-NMR) were used to separate and identify the structure of anthocyanins present in these species. Combination of LC-MS and LC-NMR data resulted in the identification of 33 anthocyanins. In particular, newly reported cis isomers of p-coumaric-derivatives were identified (petunidin-, peonidin- and malvidin-3-(6-p-coumaroyl)-5-diglucoside). In V. cinerea and V. vinifera, anthocyanins were monoglucoside derivatives whereas in V. amurensis and V. X champinii, both mono- and diglucoside derivatives were identified. Malvidin-, delphinidin- and petunidin-derivatives were, respectively, the most abundant components in V. cinerea and V. vinifera, V. amurensis and V. X champinii.
Assuntos
Antocianinas/análise , Cromatografia Líquida de Alta Pressão , Espectroscopia de Ressonância Magnética , Espectrometria de Massas por Ionização por Electrospray , Vitis/química , Glucosídeos/químicaRESUMO
Abnormal ß-amyloid peptide accumulation and aggregation is considered to be responsible for the formation and cerebral deposition of senile plaques in the brains of patients with Alzheimer's disease (AD). Inhibition of the formation of ß-amyloid (Aß) fibrils would be an attractive therapeutic target for the treatment of AD. Resveratrol and its derivatives exhibit a broad range of pharmacological properties such as protection against cardiovascular diseases and cancers, as well as promoting antiaging effects. We reported previously that ε-viniferin glucoside (VG), a resveratrol-derived dimer, strongly inhibits Aß (25-35) fibril formation in vitro. In this study, we investigated the effects of VG on the aggregation of the full-length peptides (Aß (1-40) and Aß (1-42)) and on the ß-amyloid-induced toxicity in PC12 cells. VG inhibited Aß cytotoxicity and the non-covalent complex between VG and Aß was observed by electrospray ionization mass spectrometry.
Assuntos
Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Benzofuranos/farmacologia , Estilbenos/farmacologia , Vitis/química , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Benzofuranos/isolamento & purificação , Humanos , Células PC12 , Ratos , Espectrometria de Massas por Ionização por Electrospray , Estilbenos/isolamento & purificaçãoRESUMO
Analysis of wines from different grape varieties marked by sometimes intense aromatic nuances of fresh mushroom was performed by gas chromatography coupled with olfactometry. This analysis has led to the identification of several odoriferous zones, which were recalling a fresh mushroom odor. Two trace compounds responsible for these odoriferous zones, 1-nonen-3-one and 1-octen-3-one, have been identified and their content has been determined by using either a multidimensional gas chromatography technique coupled to olfactometry and mass spectrometry detection (in the case of 1-nonen-3-one) or the preparation of the derivative with O-2,3,4,5,6-pentafluorobenzylhydroxylamine hydrochloride in the presence of the deuterated form, as the internal standard (in the case of 1-octen-3-one), then gas chromatography coupled to mass spectrometry detection. The assays allowed the quantification of these compounds at concentration levels sometimes well above their detection and recognition olfactory threshold. We show that adding nitrogen compounds to the altered wines, such as an amino acid (glycine) or a tripeptide (glutathione), led to lower concentrations of 1-octen-3-one in wines and diminished smell of fresh mushrooms. The study of the reaction in a model medium, whose composition is close to wine, by liquid chromatography coupled to mass spectrometry demonstrated the formation of adducts between 1-octen-3-one and glycine, and 1-octen-3-one and glutathione characterized by NMR.
Assuntos
Agaricales , Nitrogênio/química , Odorantes/análise , Olfato , Paladar , Vinho/análise , Cromatografia Gasosa , Cromatografia Gasosa-Espectrometria de Massas , Cetonas/análiseRESUMO
Stilbenoid compounds consist of a family of resveratrol derivatives. They have demonstrated promising activities in vitro and in vivo that indicate they may be useful in the prevention of a wide range of pathologies, such as cardiovascular diseases and cancers, as well have anti-aging effects. More recently stilbenoid compounds have shown promise in the treatment and prevention of neurodegenerative disorders, such as Huntington's, Parkinson's, and Alzheimer's diseases. This paper primarily focuses on the impact of stilbenoids in Alzheimer's disease and more specifically on the inhibition of ß-amyloid peptide aggregation.
Assuntos
Doenças Neurodegenerativas/prevenção & controle , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Estilbenos/metabolismo , Estilbenos/uso terapêutico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Doença de Alzheimer/prevenção & controle , Animais , Humanos , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/química , Resveratrol , Estilbenos/químicaRESUMO
Twenty stilbene derivatives and moracin M extracted from natural products were tested against amyloid-beta peptide (Abeta) aggregation. Results of stilbene monomer derivatives indicated that interaction with resveratrol and piceid was specific. Concerning oligomers, scirpusin A and epsilon-viniferin glucoside demonstrated a strong inhibition of the aggregation process.
Assuntos
Amiloide/química , Estilbenos/química , DimerizaçãoRESUMO
Serotonin 5-HT(4) receptor (5-HT(4)R) agonists are of particular interest for the treatment of Alzheimer's disease because of their ability to ameliorate cognitive deficits and to modulate production of amyloid beta-protein (Abeta). However, despite the range of 5-HT(4)R agonists synthesized to date, potent and selective 5-HT(4)R agonists are still lacking. In the present study, two libraries of molecules based on the scaffold of ML10302, a highly specific and partial 5-HT(4)R agonist, were efficiently prepared by parallel supported synthesis and their binding affinities and agonist activities evaluated. Furthermore, we showed that, in vivo, the two best candidates exhibited neuroprotective activity by increasing the level of the soluble form of the amyloid precursor protein (sAPPalpha) in the cortex and hippocampus of mice. Interestingly, one of these compounds could also inhibit Abeta fibril formation in vitro.