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1.
Nutrients ; 11(11)2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31683529

RESUMO

Some functional food components may help maintain homeostasis by promoting balanced gut microbiota. Here, we explore the possible complementary effects of d-fagomine and ω-3 polyunsaturated fatty acids (ω-3 PUFAs) eicosapentaenoic acid/docosahexaenoic acid (EPA/DHA 1:1) on putatively beneficial gut bacterial strains. Male Sprague-Dawley rats were supplemented with d-fagomine, ω-3 PUFAs, or both, for 23 weeks. Bacterial subgroups were evaluated in fecal DNA by quantitative real-time polymerase chain reaction (qRT-PCR) and short-chain fatty acids were determined by gas chromatography. We found that the populations of the genus Prevotella remained stable over time in animals supplemented with d-fagomine, independently of ω-3 PUFA supplementation. Animals in these groups gained less weight than controls and rats given only ω-3 PUFAs. d-Fagomine supplementation together with ω-3 PUFAs maintained the relative populations of Bacteroides. ω-3 PUFAs alone or combined with d-fagomine reduced the amount of acetic acid and total short-chain fatty acids in feces. The plasma levels of pro-inflammatory arachidonic acid derived metabolites, triglycerides and cholesterol were lower in both groups supplemented with ω-3 PUFAs. The d-fagomine and ω-3 PUFAs combination provided the functional benefits of each supplement. Notably, it helped stabilize populations of Prevotella in the rat intestinal tract while reducing weight gain and providing the anti-inflammatory and cardiovascular benefits of ω-3 PUFAs.


Assuntos
Peso Corporal/efeitos dos fármacos , Ácidos Graxos Ômega-3/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Imino Piranoses/farmacologia , Administração Oral , Animais , Bacteroides/efeitos dos fármacos , Suplementos Nutricionais , Fagopyrum/química , Ácidos Graxos Ômega-3/administração & dosagem , Imino Piranoses/administração & dosagem , Masculino , Prevotella/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Alimentos Marinhos
2.
Molecules ; 24(2)2019 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-30669468

RESUMO

A series of simple C-alkyl pyrrolidines already known as cytotoxic inhibitors of ceramide glucosylation in melanoma cells can be converted into their corresponding 6-membered analogues by means of a simple ring expansion. This study illustrated how an isomerisation from iminosugar pyrrolidine toward piperidine could invert their targeting from glucosylceramide (GlcCer) formation toward GlcCer hydrolysis. Thus, we found that the 5-membered ring derivatives did not inhibit the hydrolysis reaction of GlcCer catalysed by lysosomal ß-glucocerebrosidase (GBA). On the other hand, the ring-expanded C-alkyl piperidine isomers, non-cytotoxic and inactive regarding ceramide glucosylation, revealed to be potent inhibitors of GBA. A molecular docking study showed that the positions of the piperidine ring of the compound 6b and its analogous 2-O-heptyl DIX 8 were similar to that of isofagomine. Furthermore, compound 6b promoted mutant GBA enhancements over 3-fold equivalent to that of the related O-Hept DIX 8 belonging to one of the most potent iminosugar-based pharmacological chaperone series reported to date.


Assuntos
Ceramidas/química , Inibidores Enzimáticos/química , Glucosilceramidase/antagonistas & inibidores , Imino Açúcares/química , Animais , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Glucosilceramidase/metabolismo , Humanos , Hidrólise , Imino Piranoses/química , Isomerismo , Lisossomos , Melanoma Experimental , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Piperidinas/química , Ligação Proteica , Pirrolidinas/química , Relação Estrutura-Atividade
3.
Nat Prod Res ; 33(8): 1182-1190, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29862842

RESUMO

Metabolism, transformation and dynamic changes of DNJ, 2-O-α-D-Gal-DNJ, fagomine, isofagomine and 4-O-ß-d-Glc-fagomine from mulberry leaves in silkworms at different instars were observed. UPLC-Q/TOF-MS and UPLC-TQ/MS methods were adopted for qualitative and quantitative analysis respectively. Three species mulberry leaves were used to feed the silkworm as controls. By analyzing and comparing the content changes of DNJ, fagomine and their derivatives in silkworms and silkworm excrement at different instar, we revealed the dynamic changes, confirmed the enrichment effect of the polyhydroxy alkaloids by silkworm, and inferred the conversion process behind this effect. The experimental results indicated that DNJ and its derivatives turned into some intermediate substances in the metabolic process, and finally they converted back and the content increased. Fagomine and its derivatives interconverted into each other in the process, 4-O-ß-d-Glc-fagomine transformed into fagomine, while fagomine transformed into isofagomine.


Assuntos
Alcaloides/metabolismo , Ração Animal/análise , Bombyx/metabolismo , Morus/metabolismo , Animais , Biotransformação , Bombyx/química , Bombyx/fisiologia , Cromatografia Líquida de Alta Pressão , Imino Piranoses/análise , Imino Piranoses/metabolismo , Espectrometria de Massas , Folhas de Planta/metabolismo
4.
Bioorg Med Chem ; 26(20): 5462-5469, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30270003

RESUMO

(5aR)-5a-C-pentyl-4-epi-isofagomine 1 is a powerful inhibitor of lysosomal ß-galactosidase and a remarkable chaperone for mutations associated with GM1-gangliosidosis and Morquio disease type B. We report herein an improved synthesis of this compound and analogs (5a-C-methyl, pentyl, nonyl and phenylethyl derivatives), and a crystal structure of a synthetic intermediate that confirms its configuration resulting from the addition of a Grignard reagent. These compounds were evaluated as glycosidase inhibitors and their potential as chaperones for mutant lysosomal galactosidases determined. Based on these results and on docking studies, the 5-C-pentyl derivative 1 was selected as the optimal structure for further investigations: this compound induces the maturation of mutated ß-galactosidase in fibroblasts of a GM1-gangliosidosis patient and promote the decrease of keratan sulfate and oligosaccharide load in patient cells. Compound 1 is clearly capable of restoring ß-galactosidase activity and of promoting maturation of the protein, which should result in significant clinical benefit. These properties strongly support the development of compound 1 for the treatment of GM1-gangliosidosis and Morquio disease type B patients harboring ß-galactosidase mutations sensitive to pharmacological chaperoning.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Gangliosidose GM1/tratamento farmacológico , Imino Piranoses/química , Imino Piranoses/farmacologia , Mucopolissacaridose IV/tratamento farmacológico , beta-Galactosidase/antagonistas & inibidores , Descoberta de Drogas , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/uso terapêutico , Gangliosidose GM1/enzimologia , Gangliosidose GM1/genética , Gangliosidose GM1/metabolismo , Humanos , Imino Piranoses/síntese química , Imino Piranoses/uso terapêutico , Simulação de Acoplamento Molecular , Mucopolissacaridose IV/enzimologia , Mucopolissacaridose IV/genética , Mucopolissacaridose IV/metabolismo , Mutação/efeitos dos fármacos , Relação Estrutura-Atividade , beta-Galactosidase/genética , beta-Galactosidase/metabolismo
5.
Biosci Rep ; 38(5)2018 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-30143583

RESUMO

How glia affect neurite outgrowth during neural development has not been well elucidated. In the present study, we found that disruption of lactate production using 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) and isofagomine significantly interfered with neurite outgrowth and that exogenous application of L-lactate rescued neurite growth failure. Monocarboxylate transporter-2-knockout, which blocked the lactate shuttle in neurons, showed a remarkable decrease in the length of axons and dendrites. We further demonstrated that Akt activity was decreased while glycogen synthase kinase 3ß (GSK3ß) activity was increased after astrocytic glycogen phosphorylase blockade. Additionally, GSK3ßSer9 mutation reversed neurite growth failure caused by DAB and isofagomine. Our results suggested that lactate transportation played a critical role in neural development and disruption of the lactate shuttle in quiescent condition also affected neurite outgrowth in the central nervous system.


Assuntos
Glicogênio Sintase Quinase 3 beta/genética , Ácido Láctico/metabolismo , Transportadores de Ácidos Monocarboxílicos/genética , Neurogênese/genética , Animais , Arabinose/farmacologia , Astrócitos/efeitos dos fármacos , Axônios/enzimologia , Axônios/metabolismo , Transporte Biológico/genética , Imino Furanoses/farmacologia , Imino Piranoses/farmacologia , Neuritos/metabolismo , Neurogênese/efeitos dos fármacos , Neuroglia/efeitos dos fármacos , Neuroglia/metabolismo , Crescimento Neuronal/genética , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fosfatidilinositol 3-Quinases , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/genética , Ratos , Transdução de Sinais/efeitos dos fármacos , Álcoois Açúcares/farmacologia
6.
Mol Nutr Food Res ; 62(16): e1800373, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29979820

RESUMO

SCOPE: The goals of this work are to test if d-fagomine, an iminosugar that reduces body weight gain, can delay the appearance of a fat-induced prediabetic state in a rat model and to explore possible mechanisms behind its functional action. METHODS AND RESULTS: Wistar Kyoto rats were fed a high-fat diet supplemented with d-fagomine (or not, for comparison) or a standard diet (controls) for 24 weeks. The variables measured were fasting blood glucose and insulin levels; glucose tolerance; diacylglycerols as intracellular mediators of insulin resistance in adipose tissue (AT), liver, and muscle; inflammation markers (plasma IL-6 and leptin, and liver and AT histology markers); eicosanoids from arachidonic acid as lipid mediators of inflammation; and the populations of Bacteroidetes, Firmicutes, Enterobacteriales, and Bifidobacteriales in feces. It was found that d-fagomine reduces fat-induced impaired glucose tolerance, inflammation markers, and mediators (hepatic microgranulomas and lobular inflammation, plasma IL-6, prostaglandin E2 , and leukotriene B4 ) while attenuating the changes in the populations of Enterobacteriales and Bifidobacteriales. CONCLUSION: d-Fagomine delays the development of a fat-induced prediabetic state in rats by reducing low-grade inflammation. We suggest that the anti-inflammatory effect of d-fagomine may be linked to a reduction in fat-induced overpopulation of minor gut bacteria.


Assuntos
Fagopyrum/química , Imino Piranoses/farmacologia , Estado Pré-Diabético/prevenção & controle , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Animais , Glicemia/análise , Peso Corporal , Dieta Hiperlipídica , Microbioma Gastrointestinal , Imino Piranoses/administração & dosagem , Inflamação/prevenção & controle , Insulina/sangue , Lipídeos/sangue , Masculino , Ratos , Ratos Endogâmicos WKY
7.
J Agric Food Chem ; 66(11): 2758-2764, 2018 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-29489344

RESUMO

d-Fagomine, an analogue of 1-deoxynojirimycin (DNJ), has been shown to have hypoglycemic activity. This study is aimed at investigating if d-fagomine could attenuate high glucose-induced oxidative stress in human umbilical vein endothelial cells (HUVECs) and elucidate the underlying mechanism. Our results showed that d-fagomine reduced intracellular reactive oxygen species (ROS) production and malondialdehyde (MDA) levels. It also reversed the decrease of superoxide dismutases (SOD) and glutathione reductase (GR) activity, suggesting an inhibitory effect of d-fagomine on oxidative damage in HUVECs. d-Fagomine restored the loss of mitochondrial membrane potential, implying its protective role on mitochondrial function. In addition, d-fagomine activated the AMPK signaling pathway through LKB1, increased the expression of SIRT1 and PGC-1α, and attenuated the inhibitory effect on SIRT1 and PGC-1α activity caused by AMPK and SIRT1 inhibitor. d-Fagomine attenuated high glucose-induced oxidative stress in HUVECs through the AMPK/SIRT1/PGC-1α pathway.


Assuntos
Glucose/efeitos adversos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Imino Piranoses/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Sobrevivência Celular/efeitos dos fármacos , Glucose/metabolismo , Glutationa Redutase/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Malondialdeído/metabolismo , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Superóxido Dismutase/metabolismo , Regulação para Cima/efeitos dos fármacos
8.
Food Chem ; 251: 110-114, 2018 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-29426416

RESUMO

A rapid, sensitive, and validated method was developed for the simultaneous determination of four iminosugars, 1-deoxynojirimycin (DNJ), d-fagomine (FAG), 2-O-a-d-galactopyranosyl-DNJ (Gal-DNJ), and 4-O-ß-d-glucopyranosyl-fagomine (Glu-FAG), in mulberry leaves. The method used hydrophilic interaction chromatography coupled with tandem mass spectrometry. Based on this method, the seasonal variations of iminosugars in the leaves of different mulberry species (Morus alba, Morus multicaulis Perr, Morus atropurpurea Roxb. and Morus wittiorum Hand-Mazz.) collected in Guangzhou, China, during 10 consecutive months in 2013 were investigated. The results indicated that the maximum content of DNJ in the leaves of all four species occurred in summer (June or July). The highest FAG level was found in spring (April or May). The highest levels of Gal-DNJ and Glu-FAG were recorded in autumn (September or October).


Assuntos
Cromatografia Líquida/métodos , Imino Açúcares/análise , Morus/química , Folhas de Planta/química , Espectrometria de Massas em Tandem/métodos , 1-Desoxinojirimicina/análise , China , Interações Hidrofóbicas e Hidrofílicas , Imino Piranoses/análise , Limite de Detecção , Morus/metabolismo , Folhas de Planta/metabolismo , Reprodutibilidade dos Testes , Estações do Ano , Sensibilidade e Especificidade
9.
ACS Chem Biol ; 12(7): 1830-1841, 2017 07 21.
Artigo em Inglês | MEDLINE | ID: mdl-28485919

RESUMO

Glucocerebrosidase (GBA) is a lysosomal ß-glucosidase that degrades glucosylceramide. Its deficiency results in Gaucher disease (GD). We examined the effects of active site occupancy of GBA on its structural stability. For this, we made use of cyclophellitol-derived activity-based probes (ABPs) that bind irreversibly to the catalytic nucleophile (E340), and for comparison, we used the potent reversible inhibitor isofagomine. We demonstrate that cyclophellitol ABPs improve the stability of GBA in vitro, as revealed by thermodynamic measurements (Tm increase by 21 °C), and introduce resistance to tryptic digestion. The stabilizing effect of cell-permeable cyclophellitol ABPs is also observed in intact cultured cells containing wild-type GBA, N370S GBA (labile in lysosomes), and L444P GBA (exhibits impaired ER folding): all show marked increases in lysosomal forms of GBA molecules upon exposure to ABPs. The same stabilization effect is observed for endogenous GBA in the liver of wild-type mice injected with cyclophellitol ABPs. Stabilization effects similar to those observed with ABPs were also noted at high concentrations of the reversible inhibitor isofagomine. In conclusion, we provide evidence that the increase in cellular levels of GBA by ABPs and by the reversible inhibitor is in part caused by their ability to stabilize GBA folding, which increases the resistance of GBA against breakdown by lysosomal proteases. These effects are more pronounced in the case of the amphiphilic ABPs, presumably due to their high lipophilic potential, which may promote further structural compactness of GBA through hydrophobic interactions. Our study provides further rationale for the design of chaperones for GBA to ameliorate Gaucher disease.


Assuntos
Domínio Catalítico/fisiologia , Estabilidade Enzimática/fisiologia , Glucosilceramidase/química , Glucosilceramidase/metabolismo , Imino Piranoses/metabolismo , Animais , Sítios de Ligação , Estabilidade Enzimática/efeitos dos fármacos , Imino Piranoses/química , Imino Piranoses/farmacologia , Fígado/efeitos dos fármacos , Fígado/enzimologia , Camundongos , Estrutura Molecular , Temperatura
10.
J Agric Food Chem ; 65(22): 4414-4420, 2017 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-28489364

RESUMO

d-Fagomine is an iminosugar found in buckwheat that is capable of inhibiting the adhesion of potentially pathogenic bacteria to epithelial mucosa and reducing the postprandial blood glucose concentration. This paper evaluates the excretion and metabolism of orally administered d-fagomine in rats and compares outcomes with the fate of 1-deoxynojirimycin. d-Fagomine and 1-deoxynojirimycin show similar absorption and excretion kinetics. d-Fagomine is partly absorbed (41-84%, dose of 2 mg/kg of body weight) and excreted in urine within 8 h, while the non-absorbed fraction is cleared in feces within 24 h. d-Fagomine is partially methylated (about 10% in urine and 3% in feces). The concentration of d-fagomine in urine from 1 to 6 h after administration is higher than 10 mg/L, the concentration that inhibits adhesion of Escherichia coli. Orally administered d-fagomine is partially absorbed and then rapidly excreted in urine, where it reaches a concentration that may be protective against urinary tract infections.


Assuntos
Fagopyrum/química , Imino Piranoses/farmacocinética , Extratos Vegetais/farmacocinética , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão , Imino Piranoses/administração & dosagem , Imino Piranoses/urina , Masculino , Espectrometria de Massas , Extratos Vegetais/administração & dosagem , Extratos Vegetais/urina , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual
11.
Carbohydr Res ; 442: 31-40, 2017 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-28288345

RESUMO

By Morita-Baylis-Hillman reaction of 2,3-O-isopropylidene-D-glyceraldehyde with α,ß-unsaturated carbonyl as well as hetero analogous carbonyl compounds such as acrylonitrile, suitable precursors of isofagomine and of 4-epi-isofagomine are available. Elaboration of the structures by amine introduction, followed by intramolecular ring closure and subsequent hydroboration of the double bond provides 4-epi-isofagomine derivatives featuring chain extensions at C-5a which are determined by the structures of the carbonyl compounds employed. As an example, the synthesis of C-(5aR)- and C-(5aS)-5a-C-pentyl-4-epi-isofagomines, powerful inhibitors of ß-galactosidases, is outlined. In line with reported data, the (C-5aR) epimer was found a highly potent experimental pharmacological chaperone for GM1-associated human lysosomal ß-galactosidase mutant R201C.


Assuntos
Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Imino Piranoses/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glicosídeo Hidrolases/metabolismo , Humanos , Imino Piranoses/síntese química , Imino Piranoses/química , Lisossomos/enzimologia , Estrutura Molecular , Relação Estrutura-Atividade
12.
Eur J Med Chem ; 126: 160-170, 2017 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-27750150

RESUMO

This report is about the identification, synthesis and initial biological characterization of derivatives of 4-epi-isofagomine as pharmacological chaperones (PC) for human lysosomal ß-galactosidase. The two epimers of 4-epi-isofagomine carrying a pentyl group at C-5a, namely (5aR)- and (5aS)-5a-C-pentyl-4-epi-isofagomine, were prepared by an innovative procedure involving in the key step the addition of nitrohexane to a keto-pentopyranoside. Both epimers were evaluated as inhibitors of the human ß-galactosidase: the (5aR)-stereoisomer (compound 1) was found to be a very potent inhibitor of the enzyme (IC50 = 8 nM, 30× more potent than 4-epi-isofagomine at pH 7.3) with a high selectivity for this glycosidase whereas the (5aS) epimer was a much weaker inhibitor. In addition, compound 1 showed a remarkable activity as a PC. It significantly enhanced the residual activity of mutant ß-galactosidase in 15 patient cell lines out of 23, with enhancement factors greater than 3.5 in 10 cell lines and activity restoration up to 91% of normal. Altogether, these results indicated that (5aR)-5a-C-pentyl-4-epi-isofagomine constitutes a promising PC-based drug candidate for the treatment of GM1-gangliosidosis and Morquio disease type B.


Assuntos
Inibidores Enzimáticos/farmacologia , Gangliosidose GM1/genética , Imino Piranoses/farmacologia , Lisossomos/enzimologia , Mucopolissacaridose IV/genética , Mutação , beta-Galactosidase/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Fibroblastos/efeitos dos fármacos , Gangliosidose GM1/enzimologia , Gangliosidose GM1/patologia , Temperatura Alta , Humanos , Concentração de Íons de Hidrogênio , Imino Piranoses/síntese química , Imino Piranoses/química , Mucopolissacaridose IV/enzimologia , Mucopolissacaridose IV/patologia , Desnaturação Proteica , beta-Galactosidase/química , beta-Galactosidase/genética , beta-Galactosidase/metabolismo
13.
Sci Rep ; 6: 31380, 2016 08 19.
Artigo em Inglês | MEDLINE | ID: mdl-27539639

RESUMO

GBA gene mutations are the greatest cause of Parkinson disease (PD). GBA encodes the lysosomal enzyme glucocerebrosidase (GCase) but the mechanisms by which loss of GCase contributes to PD remain unclear. Inhibition of autophagy and the generation of endoplasmic reticulum (ER) stress are both implicated. Mutant GCase can unfold in the ER and be degraded via the unfolded protein response, activating ER stress and reducing lysosomal GCase. Small molecule chaperones that cross the blood brain barrier help mutant GCase refold and traffic correctly to lysosomes are putative treatments for PD. We treated fibroblast cells from PD patients with heterozygous GBA mutations and Drosophila expressing human wild-type, N370S and L444P GBA with the molecular chaperones ambroxol and isofagomine. Both chaperones increased GCase levels and activity, but also GBA mRNA, in control and mutant GBA fibroblasts. Expression of mutated GBA in Drosophila resulted in dopaminergic neuronal loss, a progressive locomotor defect, abnormal aggregates in the ER and increased levels of the ER stress reporter Xbp1-EGFP. Treatment with both chaperones lowered ER stress and prevented the loss of motor function, providing proof of principle that small molecule chaperones can reverse mutant GBA-mediated ER stress in vivo and might prove effective for treating PD.


Assuntos
Glucosilceramidase/genética , Chaperonas Moleculares/administração & dosagem , Mutação , Doença de Parkinson/tratamento farmacológico , Ambroxol/administração & dosagem , Ambroxol/farmacologia , Animais , Modelos Animais de Doenças , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/patologia , Drosophila melanogaster/genética , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Humanos , Imino Piranoses/administração & dosagem , Imino Piranoses/farmacologia , Chaperonas Moleculares/farmacologia , Doença de Parkinson/genética , Doença de Parkinson/patologia
15.
Eur J Med Chem ; 123: 14-20, 2016 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-27474919

RESUMO

A unique molecular library consisting of all sixteen synthetic ADMDP (1-aminodeoxy-DMDP) stereoisomers has been prepared and evaluated for inhibitory activity against α-Gal A, and ability to impart thermal stabilization of this enzyme. The results of this testing led us to develop a novel pharmacological chaperone for the treatment of Fabry disease. 3-Epimer ADMDP was found to be an effective pharmacological chaperone, able to rescue α-Gal A activity in the lymphoblast of the N215S Fabry patient-derived cell line, without impairment of cellular ß-galactosidase activity. When 3-epimer ADMDP was administered with rh-α-Gal A (enzyme replacement therapy) for the treatment of Fabry patient-derived cell lines, improvements in the efficacy of rh-α-Gal A was observed, which suggests this small molecule can also provide clinical benefit of enzyme replacement therapy in Fabry disease.


Assuntos
Terapia de Reposição de Enzimas/métodos , Doença de Fabry/tratamento farmacológico , Imino Açúcares/farmacologia , Pirrolidinas/farmacologia , alfa-Galactosidase/efeitos dos fármacos , Linhagem Celular Tumoral , Inibidores Enzimáticos/química , Estabilidade Enzimática/efeitos dos fármacos , Humanos , Imino Piranoses/química , Imino Piranoses/farmacologia , Imino Piranoses/uso terapêutico , Imino Açúcares/síntese química , Imino Açúcares/uso terapêutico , Manitol/análogos & derivados , Manitol/química , Manitol/farmacologia , Manitol/uso terapêutico , Pirrolidinas/síntese química , Pirrolidinas/uso terapêutico , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Estereoisomerismo
16.
Carbohydr Res ; 429: 71-80, 2016 Jun 24.
Artigo em Inglês | MEDLINE | ID: mdl-27063389

RESUMO

From an easily available partially protected analog of 1-deoxy-L-gulo-nojirimycin, by chain-branching at C-4 and suitable modification, lipophilic analogs of the powerful ß-D-galactosidase inhibitor 4-epi-isofagomine have been prepared. New compounds exhibit considerably improved inhibitory activities when compared with the unsubstituted parent compound and may serve as leads toward new pharmacological chaperones for GM1-gangliosidosis and Morquio B disease.


Assuntos
1-Desoxinojirimicina/análogos & derivados , Imino Piranoses/síntese química , beta-Galactosidase/antagonistas & inibidores , 1-Desoxinojirimicina/química , Gangliosidose GM1/tratamento farmacológico , Humanos , Interações Hidrofóbicas e Hidrofílicas , Imino Piranoses/química , Mucopolissacaridose IV/tratamento farmacológico , beta-Galactosidase/química
17.
Food Chem ; 204: 62-9, 2016 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-26988476

RESUMO

Pressurized liquid extraction of Aglaonema sp. iminosugars has been optimized. A single cycle under optimal conditions (80mg, 100°C, 2min) was enough to extract ⩾96% of most iminosugars. Further incubation with Saccharomyces cerevisiae for 5h removed coextracted interfering low molecular weight carbohydrates from extracts of different Aglaonema cultivars. A complete characterization of these extracts was carried out by gas chromatography-mass spectrometry: three iminosugars were tentatively identified for the first time; α-homonojirimycin and 2,5-dideoxy-2,5-imino-d-mannitol were the major iminosugars determined. α-Glucosidase inhibition activity, cell viability and thermal stability of Aglaonema extracts were also evaluated. Extracts with IC50 for α-glucosidase activity in the 0.010-0.079mgmL(-1) range showed no decrease of Caco-2 cell viability at concentrations lower than 125µgmL(-1) and were stable at 50°C for 30days. These results highlight the potential of Aglaonema extracts as a source of bioactives to be used as functional ingredients.


Assuntos
Araceae/química , Sobrevivência Celular/efeitos dos fármacos , Inibidores de Glicosídeo Hidrolases/análise , Extratos Vegetais/análise , 1-Desoxinojirimicina/análogos & derivados , 1-Desoxinojirimicina/análise , Células CACO-2 , Carboidratos/química , Fenômenos Químicos , Cromatografia Gasosa-Espectrometria de Massas , Inibidores de Glicosídeo Hidrolases/farmacologia , Humanos , Imino Piranoses/análise , Manitol/análogos & derivados , Manitol/análise , Peso Molecular , Extratos Vegetais/farmacologia , Pressão , alfa-Glucosidases/metabolismo
18.
Bioorg Med Chem Lett ; 26(5): 1438-42, 2016 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-26838810

RESUMO

From an easily available partially protected formal derivative of 1-deoxymannojirimycin, by hydroxymethyl chain-branching and further elaboration, lipophilic analogs of the powerful ß-d-galactosidase inhibitor 4-epi-isofagomine have become available. New compounds exhibit improved inhibitory activities comparable to benchmark compound NOEV (N-octyl-epi-valienamine) and may serve as leads towards improved and more selective pharmacological chaperones for GM1-gangliosidosis.


Assuntos
Inibidores Enzimáticos/farmacologia , Gangliosidose GM1/enzimologia , Imino Piranoses/farmacologia , Lisossomos/enzimologia , beta-Galactosidase/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Gangliosidose GM1/patologia , Humanos , Imino Piranoses/síntese química , Imino Piranoses/química , Lisossomos/efeitos dos fármacos , Modelos Moleculares , Estrutura Molecular , Relação Estrutura-Atividade , beta-Galactosidase/metabolismo
19.
Carbohydr Res ; 420: 6-12, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26717544

RESUMO

Electrophilic fluorination of an exocyclic methoxymethylene enol ether derived from N-tert-butyloxycarbonyl-1,5-dideoxy-1,5-imino-3,4-O-isopropylidene-D-erythro-pent-2-ulose (11) provided the 5-fluoro derivative of the powerful ß-galactosidase inhibitor 4-epi-isofagomine (8). This structural alteration, in combination with N-alkylation, led to considerably improved α-galactosidase selectivity. New compounds may serve as leads en route to new pharmacological chaperones for Fabry's disease.


Assuntos
Inibidores Enzimáticos/síntese química , Galactosidases/antagonistas & inibidores , Imino Piranoses/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Doença de Fabry/tratamento farmacológico , Doença de Fabry/enzimologia , Gangliosidose GM1/tratamento farmacológico , Gangliosidose GM1/enzimologia , Halogenação , Humanos , Imino Piranoses/química , Imino Piranoses/farmacologia , Estrutura Molecular , Relação Estrutura-Atividade
20.
Eur J Med Chem ; 121: 880-891, 2016 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-26361824

RESUMO

A library of sp(2)-iminosugar conjugates derived from the piperidine iminosugar d-fagomine and the enantiomeric pyrrolidine iminosugars DAB and LAB has been generated in only two steps involving direct coupling of the fully unprotected polyhydroxylated heterocycles with isothiocyanates, to give monocyclic thiourea adducts, and further intramolecular nucleophilic displacement of the δ-located primary hydroxyl group by the thiocarbonyl sulphur atom, affording bicyclic isothioureas. These transformations led to a dramatic shift in the inhibitory selectivity from α- to ß-glucosidases, with inhibition potencies that depended strongly on the nature of the aglycone-type moiety in the conjugates. Some of the new derivatives behaved as potent inhibitors of human ß-glucocerebrosidase (GCase), the lysosomal enzyme whose dysfunction is responsible for Gaucher disease. Moreover, GCase inhibition was 10-fold weaker at pH 5 as compared to pH 7, which is generally considered as a good property for pharmacological chaperones. Surprisingly, most of the compounds strongly inhibited GCase in wild type fibroblasts at rather low concentrations, showing an unfavourable chaperone/inhibitor balance on disease-associated GCase mutants in cellulo. A structure-activity relationship analysis points to the need for keeping a contiguous triol system in the glycone moiety of the conjugates to elicit a chaperone effect. In any case, the results reported here represent a proof of concept of the utmost importance of implementing diversity-oriented strategies for the identification and optimization of potent and specific glycosidase inhibitors and chaperones.


Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fibroblastos/efeitos dos fármacos , Doença de Gaucher/patologia , Glicosídeo Hidrolases/antagonistas & inibidores , Imino Piranoses/química , Imino Açúcares/química , Humanos , Relação Estrutura-Atividade
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