Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 251
Filtrar
Mais filtros










Filtros aplicados

Base de dados
Tipo de estudo
Intervalo de ano de publicação
1.
Carbohydr Res ; 485: 107807, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31520817

RESUMO

A series of tricyclic benzimidazole-iminosugars 1(a-f) and 2(a-f) were synthesized and evaluated for their their inhibitory activities against five glycosidases. The synthesis initiated from the benzyl protected sugar (aldehyde) 5 that reacted with 1,2-diaminobenzene to afford aldo-benzimidazole 6 by the iodine-induced oxidative condensation. Then, tricyclic compound 7 was obtained in high yields of 73%-87% by the key Mitsunobu reaction through intramolecular cyclization of the unprotected OH and the NH in 6. After removal of the benzyl group in CF3SO3H, the target tricyclic benzimidazole-iminosugars 1 and 2 were achieved. The protocol was effective for the preparation of the tricyclic iminosugar in satisfactory yield. The results of the glycosidase inhibitory activities of 1 and 2 showed that three compounds derived from d-ribose exhibited specific and good inhibitory effects on ß-glucosidase. Among them, 1e-1 was the best one with IC50 value of 5.37 µM. All hydroxyl groups on ß-position would be favourable to the inhibitory activity of such tricyclic benzimidazole-iminosugars against ß-glucosidase.


Assuntos
Benzimidazóis/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Glicosídeo Hidrolases/antagonistas & inibidores , Imino Açúcares/química , Imino Açúcares/síntese química , Configuração de Carboidratos , Técnicas de Química Sintética , Inibidores Enzimáticos/farmacologia , Imino Açúcares/farmacologia , Concentração Inibidora 50 , Modelos Moleculares , Relação Estrutura-Atividade
2.
Eur J Med Chem ; 182: 111604, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31425910

RESUMO

Immunomodulatory glycolipids, among which α-galactosylceramide (KRN7000) is an iconic example, have shown strong therapeutic potential in a variety of conditions ranging from cancer and infection to autoimmune or neurodegenerative diseases. A main difficulty for those channels is that they often provoke a cytokine storm comprising both pro- and anti-inflammatory mediators that antagonize each other and negatively affect the immune response. The synthesis of analogues with narrower cytokine secretion-inducing capabilities is hampered by the intrinsic difficulty at controlling the stereochemical outcome in glycosidation reactions, particularly if targeting the α-anomer, which seriously hampers drug optimization strategies. Here we show that replacing the monosaccharide glycone by a sp2-iminosugar glycomimetic moiety allows accessing N-linked sp2-iminosugar glycolipids (sp2-IGLs) with total α-stereocontrol in a single step with no need of protecting groups or glycosidation promotors. The lipid tail has been then readily tailored by incorporating polyfluoroalkyl segments of varied lengths in view of favouring binding to the lipid binding site of the master p38 mitogen activated protein kinase (p38 MAPK), thereby polarizing the immune response in a cell-context dependent manner. The compounds have been evaluated for their antiproliferative, anti-leishmanial and anti-inflammatory activities in different cell assays. The size of the fluorous segment was found to be critical for the biological activity, probably by regulating the aggregation and membrane-crossing properties, whereas the hydroxylation profile (gluco or galacto-like) was less relevant. Biochemical and computational data further support a mechanism of action implying binding to the allosteric lipid binding site of p38 MAPK and subsequent activation of the noncanonical autophosphorylation route. The ensemble of results provide a proof of concept of the potential of sp2-IGLs as immunoregulators.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Antiprotozoários/farmacologia , Leishmania/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/antagonistas & inibidores , Animais , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/química , Antineoplásicos/síntese química , Antineoplásicos/química , Antiprotozoários/síntese química , Antiprotozoários/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Glicolipídeos/síntese química , Glicolipídeos/química , Glicolipídeos/farmacologia , Humanos , Imino Açúcares/síntese química , Imino Açúcares/química , Imino Açúcares/farmacologia , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Testes de Sensibilidade Parasitária , Fosforilação/efeitos dos fármacos , Relação Estrutura-Atividade , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
3.
Molecules ; 24(16)2019 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-31398901

RESUMO

The unique stereoelectronic properties of sp2-iminosugars enable their participation in glycosylation reactions, thereby behaving as true carbohydrate chemical mimics. Among sp2-iminosugar conjugates, the sp2-iminosugar glycolipids (sp2-IGLs) have shown a variety of interesting pharmacological properties ranging from glycosidase inhibition to antiproliferative, antiparasitic, and anti-inflammatory activities. Developing strategies compatible with molecular diversity-oriented strategies for structure-activity relationship studies was therefore highly wanted. Here we show that a reaction sequence consisting in stereoselective C-allylation followed by thiol-ene "click" coupling provides a very convenient access to α-C-glycoside sp2-IGLs. Both the glycone moiety and the aglycone tail can be modified by using sp2-iminosugar precursors with different configurational profiles (d-gluco or d-galacto in this work) and varied thiols, as well as by oxidation of the sulfide adducts (to the corresponding sulfones in this work). A series of derivatives was prepared in this manner and their glycosidase inhibitory, antiproliferative and antileishmanial activities were evaluated in different settings. The results confirm that the inhibition of glycosidases, particularly α-glucosidase, and the antitumor/leishmanicidal activities are unrelated. The data are also consistent with the two later activities arising from the ability of the sp2-IGLs to interfere in the immune system response in a cell line and cell context dependent manner.


Assuntos
Química Click , Glicolipídeos/síntese química , Glicolipídeos/farmacologia , Glicosídeos/química , Imino Açúcares/química , Compostos de Sulfidrila/química , Antiprotozoários/síntese química , Antiprotozoários/farmacologia , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glicolipídeos/química , Glicosídeo Hidrolases/antagonistas & inibidores , Glicosídeo Hidrolases/química , Humanos , Testes de Sensibilidade Parasitária
4.
Carbohydr Res ; 478: 10-17, 2019 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-31039450

RESUMO

A series of novel tricyclic quinazolinone-iminosugars 1 (a-c) were synthesized from the benzyl protected sugars through three steps. Firstly, the benzyl protected sugar (aldehyde) 5 reacted with o-aminobenzamide by the iodine-induced oxidative condensation to afford the corresponding aldo-quizanolinone 6. Secondly, through the intramolecular cyclization of the unprotected OH and the amide NH in 6, the tricyclic compounds 7 and 8 were constructed by the key Mitsunobu reaction. Finally, removal of the benzyl group gave the target tricyclic quinazolinone-iminosugars 1. The protocol was effective for the preparation of the tricyclic iminosugars in satisfactory yield. Interestingly, an unusual C-2 epimerization was observed with d-mannose and d-ribose compounds under the conditions of the Mitsunobu reaction that generated the products having the trans configuration at the C-2 and C-3 positions. Unfortunately, such tricyclic quinazolinone-iminosugars showed no inhibitory effects on the tested five glycosidases.


Assuntos
Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Imino Açúcares/farmacologia , Quinazolinonas/farmacologia , Aspergillus niger/enzimologia , Canavalia/enzimologia , Configuração de Carboidratos , Café/enzimologia , Ciclização , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Escherichia coli/enzimologia , Glicosídeo Hidrolases/metabolismo , Imino Açúcares/síntese química , Imino Açúcares/química , Prunus dulcis/enzimologia , Quinazolinonas/síntese química , Quinazolinonas/química
5.
Eur J Med Chem ; 175: 63-71, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31075609

RESUMO

In the frame of a research program aimed to explore the relationship between chirality of iminosugars and their therapeutic potential, herein we report the synthesis of N-akyl l-deoxyiminosugars and the evaluation of the anti-inflammatory properties of selected candidates for the treatment of Pseudomonas aeruginosa infections in Cystic Fibrosis (CF) lung disease. Target glycomimetics were prepared by the shortest and most convenient approach reported to date, relying on the use of the well-known PS-TPP/I2 reagent system to prepare reactive alkoxyalkyl iodides, acting as key intermediates. Iminosugars ent-1-3 demonstrated to efficiently reduce the inflammatory response induced by P. aeruginosa in CuFi cells, either alone or in synergistic combination with their d-enantiomers, by selectively inhibiting NLGase. Surprisingly, the evaluation in murine models of lung disease showed that the amount of ent-1 required to reduce the recruitment of neutrophils was 40-fold lower than that of the corresponding d-enantiomer. The remarkably low dosage of the l-iminosugar, combined with its inability to act as inhibitor for most glycosidases, is expected to limit the onset of undesired effects, which are typically associated with the administration of its d-counterpart. Biological results herein obtained place ent-1 and congeners among the earliest examples of l-iminosugars acting as anti-inflammatory agents for therapeutic applications in Cystic Fibrosis.


Assuntos
Antibacterianos/uso terapêutico , Fibrose Cística/complicações , Imino Açúcares/uso terapêutico , Infecções por Pseudomonas/complicações , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/isolamento & purificação , Animais , Antibacterianos/administração & dosagem , Antibacterianos/química , Antibacterianos/farmacologia , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacologia , Brônquios/imunologia , Brônquios/microbiologia , Brônquios/patologia , Relação Dose-Resposta a Droga , Humanos , Imino Açúcares/administração & dosagem , Imino Açúcares/química , Imino Açúcares/farmacologia , Inflamação/prevenção & controle , Concentração Inibidora 50 , Camundongos , Neutrófilos/imunologia , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Estereoisomerismo , beta-Glucosidase/antagonistas & inibidores
6.
Amino Acids ; 51(7): 991-998, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31079215

RESUMO

DMDP acetic acid [N-carboxymethyl-2,5-dideoxy-2,5-imino-D-mannitol] 5 from Stevia rebaudiana is the first isolated natural amino acid derived from iminosugars bearing an N-alkyl acid side chain; it is clear from GCMS studies that such derivatives with acetic and propionic acids are common in a broad range of plants including mulberry, Baphia, and English bluebells, but that they are very difficult to purify. Reaction of unprotected pyrrolidine iminosugars with aqueous glyoxal gives the corresponding N-acetic acids in very high yield; Michael addition of both pyrrolidine and piperidine iminosugars and that of polyhydroxylated prolines to tert-butyl acrylate give the corresponding N-propionic acids in which the amino group of ß-alanine is incorporated into the heterocyclic ring. These easy syntheses allow the identification of this new class of amino acid in plant extracts and provide pure samples for biological evaluation. DMDP N-acetic and propionic acids are potent α-galactosidase inhibitors in contrast to potent ß-galactosidase inhibition by DMDP.


Assuntos
Acetatos/síntese química , Aminoácidos/química , Glicosídeo Hidrolases/antagonistas & inibidores , Imino Açúcares/isolamento & purificação , Propionatos/síntese química , Pirrolidinas/síntese química , Stevia/química , Aminoácidos/síntese química , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Glicina/química , Glicosídeos/metabolismo , Hidroxiprolina/química , Imino Açúcares/química , Piperidinas/síntese química , alfa-Galactosidase/antagonistas & inibidores , beta-Alanina/química , beta-Galactosidase/antagonistas & inibidores
7.
Bioorg Chem ; 86: 652-664, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30825709

RESUMO

The synthesis of a library of pyrrolidine-aryltriazole hybrids through CuAAC between two epimeric dihydroxylated azidomethylpyrrolidines and differently substituted phenylacetylenes is reported. The evaluation of the new compounds as inhibitors of lysosomal ß-glucocerebrosidase showed the importance of the substitution pattern of the phenyl moiety in the inhibition. Crystallization and docking studies revealed key interactions of the pyrrolidine motif with aminoacid residues of the catalytic site while the aryltriazole moiety extended along a hydrophobic surface groove. Some of these compounds were able to increase the enzyme activity in Gaucher patient fibroblasts, acting as a new type of chemical chaperone for Gaucher disease.


Assuntos
Inibidores Enzimáticos/farmacologia , Glucosilceramidase/antagonistas & inibidores , Imino Açúcares/farmacologia , Pirrolidinas/farmacologia , Triazóis/farmacologia , Biocatálise , Linhagem Celular , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Glucosilceramidase/genética , Glucosilceramidase/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Imino Açúcares/síntese química , Imino Açúcares/química , Simulação de Acoplamento Molecular , Estrutura Molecular , Mutação , Pirrolidinas/química , Relação Estrutura-Atividade , Propriedades de Superfície , Triazóis/química
8.
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
9.
Carbohydr Res ; 472: 65-71, 2019 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-30496874

RESUMO

The Lewis acid-catalyzed nucleophilic opening of a D-gluco-configured bicyclic hemiaminal has been examined. Several Lewis acids and silylated nucleophiles have been screened allowing the introduction of acetophenone, phosphonate or nitrile at the pseudoanomeric position in satisfactory yields and high 1,2 trans stereoselectivities. Their skeletal rearrangement triggered by the N-benzyl anchimeric assistance provided the corresponding L-ido-configured piperidines displaying various functional groups at C-6 position in good yield.


Assuntos
Imino Açúcares/química , Ácidos de Lewis/química , Piperidinas/química , Compostos Bicíclicos Heterocíclicos com Pontes/química , Catálise , Estrutura Molecular , Estereoisomerismo
10.
Bioorg Chem ; 83: 424-431, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30428432

RESUMO

Inhibition of the biosynthesis of complex N-glycans in the Golgi apparatus is one of alternative ways to suppress growth of tumor tissue. Eight N-benzyl substituted 1,4-imino-l-lyxitols with basic functional groups (amine, amidine, guanidine), hydroxyl and fluoro groups were prepared, optimized their syntheses and tested for their ability to inhibit several α-mannosides from the GH family 38 (GMIIb, LManII and JBMan) as models for human Golgi and lysosomal α-mannoside II. All compounds were found to be selective inhibitors of GMIIb. The most potent structure bearing guanidine group, inhibited GMIIb at the micromolar level (Ki = 19 ±â€¯2 µM) while no significant inhibition (>2 mM) of LManII and JBMan was observed. Based on molecular docking and pKa calculations this structure may form two salt bridges with aspartate dyad of the target enzyme improving its inhibitory potency compared with other N-benzyl substituted derivatives published in this and previous studies.


Assuntos
Inibidores Enzimáticos/química , Imino Açúcares/química , Álcoois Açúcares/química , alfa-Manosidase/antagonistas & inibidores , Animais , Domínio Catalítico , Proteínas de Drosophila/antagonistas & inibidores , Proteínas de Drosophila/química , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/enzimologia , Ensaios Enzimáticos , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/metabolismo , Imino Açúcares/síntese química , Imino Açúcares/metabolismo , Simulação de Acoplamento Molecular , Ligação Proteica , Álcoois Açúcares/síntese química , Álcoois Açúcares/metabolismo , alfa-Manosidase/química , alfa-Manosidase/metabolismo
11.
Molecules ; 23(10)2018 Oct 18.
Artigo em Inglês | MEDLINE | ID: mdl-30340368

RESUMO

Some point mutations in ß-glucocerebrosidase cause either improper folding or instability of this protein, resulting in Gaucher disease. Pharmacological chaperones bind to the mutant enzyme and stabilize this enzyme; thus, pharmacological chaperone therapy was proposed as a potential treatment for Gaucher disease. The binding affinities of α-1-C-alkyl 1,4-dideoxy-1,4-imino-d-arabinitol (DAB) derivatives, which act as pharmacological chaperones for ß-glucocerebrosidase, abruptly increased upon elongation of their alkyl chain. In this study, the primary causes of such an increase in binding affinity were analyzed using protein⁻ligand docking and molecular dynamics simulations. We found that the activity cliff between α-1-C-heptyl-DAB and α-1-C-octyl-DAB was due to the shape and size of the hydrophobic binding site accommodating the alkyl chains, and that the interaction with this hydrophobic site controlled the binding affinity of the ligands well. Furthermore, based on the aromatic/hydrophobic properties of the binding site, a 7-(tetralin-2-yl)-heptyl-DAB compound was designed and synthesized. This compound had significantly enhanced activity. The design strategy in consideration of aromatic interactions in the hydrophobic pocket was useful for generating effective pharmacological chaperones for the treatment of Gaucher disease.


Assuntos
Doença de Gaucher/tratamento farmacológico , Glucosilceramidase/antagonistas & inibidores , Imino Açúcares/química , Álcoois Açúcares/química , Sítios de Ligação , Estabilidade Enzimática/efeitos dos fármacos , Glucosilceramidase/química , Humanos , Imino Açúcares/uso terapêutico , Ligantes , Chaperonas Moleculares/química , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteínas Mutantes/química , Mutação Puntual , Ligação Proteica , Álcoois Açúcares/antagonistas & inibidores , Álcoois Açúcares/uso terapêutico
12.
Antiviral Res ; 158: 113-121, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30096339

RESUMO

Despite the availability of prophylactic vaccines the burden of human papillomavirus (HPV) associated malignancy remains high and there is a need to develop additional therapeutic strategies to complement vaccination. We have previously shown that the poorly characterised E5 oncoprotein forms a virus-coded ion channel or viroporin that was sensitive to the amantadine derivative rimantadine. We now demonstrate that alkylated imino sugars, which have antiviral activity against a number of viruses, inhibit E5 channel activity in vitro. Using molecular modelling we predict that imino sugars intercalate between E5 protomers to prevent channel oligomerisation. We explored the ability of these viroporin inhibitors to block E5-mediated activation of mitogenic signalling in keratinocytes. Treatment with either rimantadine or imino sugars prevented ERK-MAPK phosphorylation and reduced cyclin B1 expression in cells expressing E5 from a number of high-risk HPV types. Moreover, viroporin inhibitors also reduced ERK-MAPK activation and cyclin B1 expression in differentiating primary human keratinocytes containing high-risk HPV18. These observations provide evidence of a key role for E5 viroporin function during the HPV life cycle. Viroporin inhibitors could be utilised for stratified treatment of HPV associated tumours prior to virus integration, or as true antiviral therapies to eliminate virus prior to malignant transformation.


Assuntos
Antivirais/farmacologia , Imino Açúcares/farmacologia , Canais Iônicos/antagonistas & inibidores , Papillomaviridae/efeitos dos fármacos , Linhagem Celular , Ciclina B1/metabolismo , Humanos , Queratinócitos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas Oncogênicas Virais/antagonistas & inibidores , Infecções por Papillomavirus/virologia , Fosforilação , Rimantadina/farmacologia , Transdução de Sinais , Proteínas Virais/antagonistas & inibidores
13.
Angew Chem Int Ed Engl ; 57(27): 8002-8006, 2018 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-29722924

RESUMO

Multivalent design of glycosidase inhibitors is a promising strategy for the treatment of diseases involving enzymatic hydrolysis of glycosidic bonds in carbohydrates. An essential prerequisite for successful applications is the atomic-level understanding of how outstanding binding enhancement occurs with multivalent inhibitors. Herein we report the first high-resolution crystal structures of the Jack bean α-mannosidase (JBα-man) in apo and inhibited states. The three-dimensional structure of JBα-man in complex with the multimeric cyclopeptoid-based inhibitor displaying the largest binding enhancements reported so far provides decisive insight into the molecular mechanisms underlying multivalent effects in glycosidase inhibition.


Assuntos
alfa-Manosidase/metabolismo , Sítios de Ligação , Canavalia/enzimologia , Domínio Catalítico , Cristalografia por Raios X , Imino Açúcares/química , Imino Açúcares/metabolismo , Estrutura Terciária de Proteína , Zinco/química , Zinco/metabolismo , alfa-Manosidase/antagonistas & inibidores
14.
Carbohydr Res ; 464: 2-7, 2018 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-29777947

RESUMO

Synthetic analogues of the naturally occurring iminosugar homoDMDP, which feature a perfluoroalkyl group at the pseudo-anomeric position, have been synthesized from the corresponding sugar-derived cyclic aldonitrone. The new fluorinated iminosugars as well as homoDMDP and its 6-deoxy counterpart were evaluated for their inhibitory activity against a panel of glycosidases. While the replacement of the (1',2')-dihydroxyethyl substituent of homoDMDP with -C4F9 proved detrimental for enzyme binding, introduction of a -C3F7 moiety tuned the inhibitory activity spectrum selectively towards α-fucosidase and α-glucosidase from yeast.


Assuntos
Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/farmacologia , Glicosídeo Hidrolases/antagonistas & inibidores , Imino Açúcares/síntese química , Imino Açúcares/farmacologia , Alquilação , Aspergillus/enzimologia , Técnicas de Química Sintética , Inibidores Enzimáticos/química , Imino Açúcares/química , Estereoisomerismo , Relação Estrutura-Atividade
15.
Eur J Med Chem ; 151: 765-776, 2018 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-29674295

RESUMO

The synthesis of three libraries (1a-l, 1a'-l' and 2a-l) of dimeric iminosugars through CuAAC reaction between three different alkynyl pyrrolidines and a set of diazides was carried out. The resulting crude dimers were screened in situ against two α-fucosidases (libraries 1a-l and 1a'-l') and one ß-galactosidase (2a-l). This method is pioneer in the search of divalent glycosidase inhibitors. It has allowed the rapid identification of dimer 1i as the best inhibitor of α-fucosidases from bovine kidney (Ki = 0.15 nM) and Homo sapiens (Ki = 60 nM), and dimer 2e as the best inhibitor of ß-galactosidase from bovine liver (Ki = 5.8 µM). In order to evaluate a possible divalent effect in the inhibition, the synthesis and biological analysis of the reference monomers were also performed. Divalent effect was only detected in the inhibition of bovine liver ß-galactosidase by dimer 2e.


Assuntos
Imino Açúcares/química , Imino Açúcares/farmacologia , Pirrolidinas/química , Pirrolidinas/farmacologia , alfa-L-Fucosidase/antagonistas & inibidores , beta-Galactosidase/antagonistas & inibidores , Animais , Bovinos , Química Click , Dimerização , Desenho de Fármacos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Humanos , Relação Estrutura-Atividade , alfa-L-Fucosidase/metabolismo , beta-Galactosidase/metabolismo
16.
Molecules ; 23(4)2018 04 17.
Artigo em Inglês | MEDLINE | ID: mdl-29673163

RESUMO

A series of sp²-iminosugar glycomimetics differing in the reducing or nonreducing character, the configurational pattern (d-gluco or l-ido), the architecture of the glycone skeleton, and the nature of the nonglycone substituent has been synthesized and assayed for their inhibition properties towards commercial glycosidases. On the basis of their affinity and selectivity towards GH1 ß-glucosidases, reducing and nonreducing bicyclic derivatives having a hydroxylation profile of structural complementarity with d-glucose and incorporating an N'-octyl-isourea or -isothiourea segment were selected for further evaluation of their inhibitory/chaperoning potential against human glucocerebrosidase (GCase). The 1-deoxynojirimycin (DNJ)-related nonreducing conjugates behaved as stronger GCase inhibitors than the reducing counterparts and exhibited potent chaperoning capabilities in Gaucher fibroblasts hosting the neuronopathic G188S/G183W mutation, the isothiourea derivative being indeed one of the most efficient chaperone candidates reported up to date (70% activity enhancement at 20 pM). At their optimal concentration, the four selected compounds promoted mutant GCase activity enhancements over 3-fold; yet, the inhibitor/chaperoning balance became unfavorable at much lower concentration for nonreducing as compared to reducing derivatives.


Assuntos
Inibidores Enzimáticos/uso terapêutico , Doença de Gaucher/tratamento farmacológico , Doença de Gaucher/enzimologia , Glucosilceramidase/antagonistas & inibidores , Glucosilceramidase/genética , Imino Açúcares/uso terapêutico , Chaperonas Moleculares/uso terapêutico , 1-Desoxinojirimicina/uso terapêutico , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Doença de Gaucher/genética , Glucosamina/análogos & derivados , Glucosamina/uso terapêutico , Humanos , Mutação
17.
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
18.
Int J Biol Macromol ; 111: 82-91, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29305216

RESUMO

In the recent decades, the interest on glycosidases has dramatically increased, mainly because these enzymes play a vital role in many biological processes. Based on the biological potential associated to these enzymes, several glycosidase inhibitors have been developed. In this review, the most important inhibitors targeting these enzymes, including the disaccharides, iminosugars, monocyclic iminosugars, bicyclic iminosugars, thiosugars and carbasugars will be discussed and special attention will be given to the ones that are currently used clinically. This review summarizes and characterizes the current knowledge regarding the classes of glycosidase inhibitors that have therapeutic potential in a wide range of diseases. It highlights the patents, relevant research and patent applications filed in the past years in the field. Since the glycosidase inhibitors are involved in several chronic diseases and possibly pandemic, the pharmaceutical research towards developing new generations of these molecules is very important to public health. Most of the glycosidase inhibitors mimics the structures of monosaccharides or oligosaccharides and are well accepted by the organisms since they benefit from privileged drug-like properties. Disaccharides, iminosugars, carbasugars and thiosugars derivatives are the most popular inhibitors among the glycosidase inhibitors.


Assuntos
Dissacarídeos/química , Inibidores Enzimáticos/química , Glicosídeo Hidrolases/química , Imino Açúcares/química , Carbaçúcares/química , Carbaçúcares/uso terapêutico , Dissacarídeos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Glicosídeo Hidrolases/antagonistas & inibidores , Humanos , Imino Açúcares/uso terapêutico , Tioaçúcares/química , Tioaçúcares/uso terapêutico
19.
ChemMedChem ; 13(4): 338-351, 2018 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-29323471

RESUMO

It is important to find more effective and safer immunosuppressants, because clinically used immunosuppressive agents have significant side effects. A series of N-substituted iminosugar derivatives were designed and synthesized, and their immunosuppressive effects were evaluated by the CCK-8 assay. The results revealed that iminosugars 10 e and 10 i, that is, (3R,4S)-1-(4-heptyloxylphenylethyl)pyrrolidine-3,4-diol and (3R,4S)-1-[2-(2-chloro-4-(p-tolylthio)-phenyl-1-yl)ethyl]pyrrolidine-3,4-diol, respectively, exhibited the strongest inhibitory effects on mouse splenocyte proliferation (IC50 =2.16 and 2.48 µm, respectively), whereas the iminosugars containing an amide group near the hydrophilic head (compounds 10 j-n) exhibited no inhibitory effects. Further studies revealed that the inhibitory effects on splenocyte proliferation may have come from the suppression of both IFN-γ and IL-4 cytokines. Our results suggest that synthetic iminosugars, especially compounds 10 e and 10 i, hold potential as immunosuppressive agents.


Assuntos
Imino Açúcares/química , Imunossupressores/síntese química , Animais , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Imino Açúcares/síntese química , Imino Açúcares/farmacologia , Imunossupressores/química , Imunossupressores/farmacologia , Interferon gama/metabolismo , Interleucina-4/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Baço/citologia , Baço/efeitos dos fármacos , Baço/metabolismo , Relação Estrutura-Atividade
20.
Bioorg Med Chem Lett ; 28(3): 425-428, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29269212

RESUMO

Novel pentacyclic iminosugars 1 and 2 with the constrained butterfly-like conformation were first synthesized by the key intramolecular click reaction from the tricyclic iminosugars fused benzo[e][1,3]thiazin-4-one 3 and 4. The pentacyclic iminosugar was constructed by fusing both benzo[e][1,3]thiazin-4-one and triazolo[5,1-c][1,4]oxazepine scaffolds. Their structures were determined by their 1H, 13C NMR, and HRMS (ESI) spectra and X-ray. The pentacyclic iminosugars 1(a-c), 2(a-b) and their corresponding protected precursors 13(a-c) and 14(a-b) were examined for their HIV reverse transcriptase (RT) inhibitory activities. The result showed that all compounds could effectively inhibit RT activity. Among them, compound 13c was the best one with the IC50 value of RT inhibitory activity of 0.69 µM. Structure-activity relationship analysis suggested that the improvement of the hydrophilicity of the pentacycles was of benefit to their anti-HIV RT activity.


Assuntos
Transcriptase Reversa do HIV/antagonistas & inibidores , Imino Açúcares/farmacologia , Inibidores da Transcriptase Reversa/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Transcriptase Reversa do HIV/metabolismo , Imino Açúcares/síntese química , Imino Açúcares/química , Modelos Moleculares , Conformação Molecular , Inibidores da Transcriptase Reversa/síntese química , Inibidores da Transcriptase Reversa/química , Relação Estrutura-Atividade
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA