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 & inibidoresRESUMO
The affinity of a series of iminosugar-based inhibitors exhibiting various ring sizes toward Hex A and their essential interactions with the enzyme active site were investigated. All the Hex A-inhibiting iminosugars tested formed hydrogen bonds with Arg178, Asp322, Tyr421 and Glu462 and had the favorable cation-π interaction with Trp460. Among them, DMDP amide (6) proved to be the most potent competitive inhibitor with a Ki value of 0.041 µM. We analyzed the dynamic properties of both DMDP amide (6) and DNJNAc (1) in aqueous solution using molecular dynamics (MD) calculations; the distance of the interaction between Asp322 and 3-OH and Glu323 and 6-OH was important for stable interactions with Hex A, reducing fluctuations in the plasticity of the active site. DMDP amide (6) dose-dependently increased intracellular Hex A activity in the G269S mutant cells and restored Hex A activity up to approximately 43% of the wild type level; this effect clearly exceeded the border line treatment for Tay-Sachs disease, which is regarded as 10-15% of the wild type level. This is a significantly greater effect than that of pyrimethamine, which is currently in Phase 2 clinical trials. DMDP amide (6), therefore, represents a new promising pharmacological chaperone candidate for the treatment of Tay-Sachs disease.
Assuntos
Domínio Catalítico , Simulação por Computador , Hexosaminidase A/metabolismo , Açúcares/metabolismo , Açúcares/farmacologia , Doença de Tay-Sachs/tratamento farmacológico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/uso terapêutico , Hexosaminidase A/antagonistas & inibidores , Hexosaminidase A/química , Hexosaminidase A/genética , Humanos , Simulação de Dinâmica Molecular , Mutação , Açúcares/química , Açúcares/uso terapêuticoRESUMO
A ring-contraction strategy applied to ß-azido,γ-hydroxyazepanes yielded after functional group manipulation new tetrahydroxylated pyrrolidines displaying an acetamido moiety, one of these iminosugars demonstrating low micromolar inhibition on N-acetylglucosaminidases.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/síntese química , Hexosaminidases/antagonistas & inibidores , Imino Açúcares/química , Imino Açúcares/síntese química , Ativação Enzimática/efeitos dos fármacos , Estrutura Molecular , PirrolidinasRESUMO
The enantiomers of XYLNAc (2-N-acetylamino-1,2,4-trideoxy-1,4-iminoxylitol) are prepared from the enantiomers of glucuronolactone; the synthesis of the enantiomers of LYXNAc (2-N-acetylamino-1,2,4-trideoxy-1,4-iminolyxitol) from an L-arabinono-δ-lactone and a D-ribono-δ-lactone is reported. A comparison is made of the inhibition of ß-N-acetylhexosaminidases (HexNAcases) and α-N-acetylgalactosaminidase (α-GalNAcase) by 8 stereoisomeric 2-N-acetylamino-1,2,4-trideoxy-1,4-iminopentitols; their N-benzyl derivatives are better inhibitors than the parent compounds. Both XYLNAc and LABNAc are potent inhibitors against HexNAcases. None of the compounds show any inhibition of α-GalNAcase.
Assuntos
Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Iminas/química , Iminas/farmacologia , Xilitol/análogos & derivados , Xilitol/síntese química , beta-N-Acetil-Hexosaminidases/antagonistas & inibidores , Fabaceae/enzimologia , Pirrolidinas/química , Estereoisomerismo , Xilitol/química , beta-N-Acetil-Hexosaminidases/metabolismoRESUMO
We report on the identification of the required configuration and binding orientation of nor-tropane alkaloid calystegines against ß-glucocerebrosidase. Calystegine B2 is a potent competitive inhibitor of human lysosomal ß-glucocerebrosidase with Ki value of 3.3 µM. A molecular docking study revealed that calystegine B2 had a favorable van der Waals interactions (Phe128, Trp179, and Phe246) and the hydrogen bonding (Glu235, Glu340, Asp127, Trp179, Asn234, Trp381 and Asn396) was similar to that of isofagomine. All calystegine isomers bound into the same active site as calystegine B2 and the essential hydrogen bonds formed to Asp127, Glu235 and Glu340 were maintained. However, their binding orientations were obviously different. Calystegine A3 bound to ß-glucocerebrosidase with the same orientations as calystegine B2 (Type 1), while calystegine B3 and B4 had different binding orientations (Type 2). It is noteworthy that Type 1 orientated calystegines B2 and A3 effectively stabilized ß-glucocerebrosidase, and consequently increased intracellular ß-glucocerebrosidase activities in N370S fibroblasts, while Type 2 orientated calystegines B3 and B4 could not keep the enzyme activity. These results clearly indicate that the binding orientations of calystegines are changed by the configuration of the hydroxyl groups on the nor-tropane ring and the suitable binding orientation is a requirement for achieving a strong affinity to ß-glucocerebrosidase.
Assuntos
Tropanos/metabolismo , Sítios de Ligação , Domínio Catalítico , Linhagem Celular , Doença de Gaucher/enzimologia , Doença de Gaucher/patologia , Glucosilceramidase/antagonistas & inibidores , Glucosilceramidase/metabolismo , Humanos , Ligação de Hidrogênio , Imino Piranoses/química , Imino Piranoses/metabolismo , Isomerismo , Simulação de Acoplamento Molecular , Nortropanos/química , Nortropanos/metabolismo , Alcaloides de Solanáceas/química , Alcaloides de Solanáceas/metabolismo , Eletricidade Estática , Relação Estrutura-Atividade , Tropanos/químicaRESUMO
All 16 stereoisomeric N-methyl 5-(hydroxymethyl)-3,4-dihydroxyproline amides have been synthesized from lactones accessible from the enantiomers of glucuronolactone. Nine stereoisomers, including all eight with a (3R)-hydroxyl configuration, are low to submicromolar inhibitors of ß-N-acetylhexosaminidases. A structural correlation between the proline amides is found with the ADMDP-acetamide analogues bearing an acetamidomethylpyrrolidine motif. The proline amides are generally more potent than their ADMDP-acetamide equivalents. ß-N-Acetylhexosaminidase inhibition by an azetidine ADMDP-acetamide analogue is compared to an azetidine carboxylic acid amide. None of the amides are good α-N-acetylgalactosaminidase inhibitors.
Assuntos
Acetamidas/química , Amidas/química , Ácido Azetidinocarboxílico/química , Prolina/análogos & derivados , Prolina/química , beta-N-Acetil-Hexosaminidases/antagonistas & inibidores , Cinética , Estereoisomerismo , beta-N-Acetil-Hexosaminidases/químicaRESUMO
Iteamine, o-aminobenzyl ß-D-glucopyranoside, is the first alkaloid to be isolated from Itea virginica. Itea is the sole plant source of D-psicose, a rare sugar likely to be a major dietary supplement. The structure of iteamine was established by NMR and confirmed by total synthesis. Iteamine and its galacto-analog (which was not found in Itea plants) showed no strong inhibition of any of the 15 glycosidases tested; unnatural galacto-iteamine was a weak inhibitor of chicken liver α-N-acetylgalactosaminidase.
Assuntos
Alcaloides/isolamento & purificação , Alcaloides/farmacologia , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Inflorescência/química , Traqueófitas/química , Alcaloides/química , Animais , Inibidores Enzimáticos/química , Glucosídeos , alfa-N-Acetilgalactosaminidase/antagonistas & inibidoresRESUMO
A series of iminoxylitol derivatives carrying a C-linked di-O-acyl or di-O-alkyl glyceryl substituent were prepared and characterized. All of these compounds, which were designed as glucosylceramide (GlcCer) mimics, were nanomolar inhibitors of lysosomal ß-glucosidase (glucocerebrosidase, GCase). Two of these pseudoglycolipids were further evaluated for their ability to enhance the activity of mutant GCase in human Gaucher cells. Although the di-O-hexyl ether was surprisingly devoid of chaperoning activity on both N370S and L444P GCases, the di-O-decanoyl ester was a potent chaperone of the L444P hydrolase, capable of increasing the residual activity of the enzyme by a factor of two at a very low concentration (50â nM); such a significant effect on the L444P mutation in human fibroblasts has not yet been observed. In heat-stress studies, the diether was found to be much more effective in stabilizing the wild-type enzyme than the diester. Four representative pseudoglycolipids were also assayed as inhibitors of GlcCer synthase, because such compounds could find use in the substrate reduction therapy approach to treat lysosomal storage diseases, but these compounds revealed only moderate activity. As efficient pharmacological chaperones, new structures such as the di-C10 -ester constitute leads for the development of therapeutic agents for typesâ 2 and 3 Gaucher disease, the most severe neuronopathic forms of this lysosomal disease.
Assuntos
Biomimética , Glucosilceramidase/antagonistas & inibidores , Glucosilceramidas/química , Chaperonas Moleculares/química , Sequência de Carboidratos , Linhagem Celular , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Fibroblastos/efeitos dos fármacos , Doença de Gaucher/enzimologia , Doença de Gaucher/genética , Glucosilceramidas/farmacologia , Humanos , Chaperonas Moleculares/farmacologia , MutaçãoRESUMO
In this study we revealed that the addition of an N-phenylacetamide substituent to the C-1 position of 1-deoxyfuconojirimycin (DFJ) can lead to highly potent inhibitors of α-l-fucosidases. A structure-activity relationship study showed that a fluoro group on the phenyl ring greatly increased its potency and selectivity. In contrast the addition of two or three fluoro groups decreased their inhibition potency. Consequently, N-(2-fluorophenyl)-2ß-DFJ acetamide (18j) was found to display very potent and selective inhibition of bovine kidney, rat epididymis, and human lysosome α-l-fucosidases, with IC50 value of 0.012, 0.044, and 0.0079µM respectively. It is noteworthy that our designed N-phenyl-2ß-DFJ acetamide derivative exhibited about 18-fold stronger effects on human lysosomal α-l-fucosidase than original DFJ and it occupied the active-site of this enzyme. We therefore expect that this compound may find applications in new therapeutic trials against genetic deficiency disorders.
Assuntos
1-Desoxinojirimicina/análogos & derivados , Acetamidas/síntese química , Inibidores Enzimáticos/síntese química , Álcoois Açúcares/química , alfa-L-Fucosidase/antagonistas & inibidores , 1-Desoxinojirimicina/síntese química , 1-Desoxinojirimicina/química , 1-Desoxinojirimicina/metabolismo , Acetamidas/química , Acetamidas/metabolismo , Animais , Domínio Catalítico , Bovinos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Epididimo/enzimologia , Humanos , Rim/enzimologia , Lisossomos/enzimologia , Masculino , Ligação Proteica , Ratos , Relação Estrutura-Atividade , alfa-L-Fucosidase/metabolismoRESUMO
Pochonicine, the first naturally occurring polyhydroxylated pyrrolizidine containing an acetamidomethyl group, which was isolated from Pochonia suchlasporia var. suchlasporia TAMA 87, together with its enantiomer and their C-1 and/or C-3 epimers, have been synthesized from the sugar-derived cyclic nitrones 9D and 9L, respectively. An in-depth NMR study showed that both the (1)H and (13)C NMR spectra of the synthetic pochonicines (1D and 1L) matched very well with those of natural pochonicine in D2O, which unequivocally determined the relative configuration of the natural product as 1D or 1L. In addition, comparison of the optical rotations of the synthetic pochonicines and that of the natural product, but more convincingly their glycosidase inhibition profiles, confirmed the absolute configuration of natural pochonicine as 1R,3S,5R,6R,7S,7aR. Thereby, the structure of natural pochonicine was unequivocally determined as (+)-(1R,3S,5R,6R,7S,7aR)-pochonicine (1D). Glycosidase inhibition experiments showed that natural pochonicine 1D and its epimers 2D, 3D, and 4D all are powerful inhibitors of hexosaminidases (five ß-N-acetylglucosaminidases and two ß-N-acetylgalactosaminidases) while their enantiomers 1L, 2L, 3L, and 4L are much weaker inhibitors of the same enzymes. (-)-3-epi-Pochonicine (2L) was found to be a potent and selective inhibitor of α-l-rhamnosidase. None of the compounds showed any inhibition of α-GalNAcase.
Assuntos
Inibidores Enzimáticos/síntese química , Alcaloides de Pirrolizidina/síntese química , beta-N-Acetil-Hexosaminidases/antagonistas & inibidores , beta-N-Acetil-Hexosaminidases/química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/isolamento & purificação , Inibidores Enzimáticos/farmacologia , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Alcaloides de Pirrolizidina/química , Alcaloides de Pirrolizidina/isolamento & purificação , Alcaloides de Pirrolizidina/farmacologia , EstereoisomerismoRESUMO
Crystal structures were obtained for the two C2 epimeric azido-γ-lactones 2-azido-2-deoxy-3,5:6,7-di-O-isopropylidene-d-glycero-d-ido-heptono-1,4-lactone and 2-azido-2-deoxy-3,5:6,7-di-O-isopropylidene-d-glycero-d-gulo-heptono-1,4-lactone prepared from kinetic and thermodynamic azide displacements of a triflate derived from d-glucoheptonolactone. Azido-γ-lactones are very useful intermediates in the synthesis of iminosugars and polyhydroxylated amino acids. In this study two epimeric azido-heptitols allow biotechnological transformations via Izumoring techniques to 8 of the 16 possible homonojirimycin analogues, 5 of which were isolated pure because of the lack of stereoselectivity of the final reductive amination. A side-by-side glycosidase inhibition profile of 11 of the possible 16 HNJ stereoisomers derived from d-glucose and d-mannose is presented.
Assuntos
1-Desoxinojirimicina/análogos & derivados , Azidas/química , Glucose/química , Lactonas/química , Termodinâmica , 1-Desoxinojirimicina/química , Cinética , Modelos Moleculares , Conformação Molecular , EstereoisomerismoRESUMO
The Ho crossed aldol condensation provides access to a series of carbon branched iminosugars as exemplified by the synthesis of enantiomeric pairs of isoDMDP, isoDGDP, and isoDAB, allowing comparison of their biological activities with three linear isomeric natural products DMDP, DGDP, and DAB and their enantiomers. L-IsoDMDP [(2S,3S,4R)-2,4-bis(hydroxymethyl)pyrrolidine-3,4-diol], prepared in 11 steps in an overall yield of 45% from d-lyxonolactone, is a potent specific competitive inhibitor of gut disaccharidases [K(i) 0.081 µM for rat intestinal maltase] and is more effective in the suppression of hyperglycaemia in a maltose loading test than miglitol, a drug presently used in the treatment of late onset diabetes. The partial rescue of the defective F508del-CFTR function in CF-KM4 cells by L-isoDMDP is compared with miglustat and isoLAB in an approach to the treatment of cystic fibrosis.
Assuntos
1-Desoxinojirimicina/análogos & derivados , Inibidores da Angiogênese/farmacologia , Produtos Biológicos/farmacologia , Inibidores Enzimáticos/farmacologia , Inibidores de Glicosídeo Hidrolases , Imino Açúcares/farmacologia , 1-Desoxinojirimicina/farmacologia , Inibidores da Angiogênese/síntese química , Inibidores da Angiogênese/química , Produtos Biológicos/síntese química , Produtos Biológicos/química , Relação Dose-Resposta a Droga , Imino Açúcares/síntese química , Imino Açúcares/química , Conformação Molecular , Estereoisomerismo , Relação Estrutura-Atividade , alfa-Glucosidases/metabolismoRESUMO
The mirror image of natural product (+)-adenophorine along with its 1-epi-, 1-homo-analogs and other derivatives have been synthesized and evaluated as glycosidase inhibitors. The synthetic strategy is based on the skeletal rearrangement of tetrahydroxylated C-alkyl azepanes obtained via a Staudinger/azaWittig/alkylation sequence starting from a sugar-derived azidolactol. Several organometallic species have been investigated for the alkylation step including organomagnesium, organolithium, organozinc, organoaluminum and organocerium reagents. While diallylzinc proved to be the most efficient to introduce an allyl substituent, disappointing results were obtained with the other organometallic species leading either to lower yields or no reaction. Enzymatic assays indicate that (-)-adenophorine is a moderate α-l-fucosidase inhibitor.
Assuntos
Compostos Aza/síntese química , Inibidores Enzimáticos/síntese química , Glicosídeo Hidrolases/antagonistas & inibidores , Imino Açúcares/química , Alquilação , Animais , Aspergillus niger/enzimologia , Compostos Aza/química , Compostos Aza/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Glicosídeo Hidrolases/metabolismo , Imino Açúcares/síntese química , Imino Açúcares/metabolismo , Oryza/enzimologia , Ligação Proteica , Ratos , Saccharomyces cerevisiae/enzimologia , Estereoisomerismo , alfa-L-Fucosidase/antagonistas & inibidores , alfa-L-Fucosidase/metabolismoRESUMO
The synthesis from l-arabinose of an azetidine analogue of 6,7-diepicastanospermine and its glycosidase inhibition profile are described.
Assuntos
1-Desoxinojirimicina/química , Arabinose/química , Azetidinas/química , Indolizinas/química , Azetidinas/síntese química , Azetidinas/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Glicosídeo Hidrolases/antagonistas & inibidores , Glicosídeo Hidrolases/metabolismo , Conformação Molecular , Ligação Proteica , EstereoisomerismoRESUMO
A general and efficient method has been developed for the synthesis of sugar-derived azepane nitrones starting from aldohexoses, with an intramolecular condensation of aldehyde and hydroxylamine as the key step. Through this strategy, each aldohexose produced a pair of azepane nitrones, which are precursors of various azepane iminosugars.
Assuntos
Carboidratos/química , Óxidos de Nitrogênio/síntese química , Estrutura Molecular , Óxidos de Nitrogênio/químicaRESUMO
The formation from D-glucose of both enantiomers of 2,4-dideoxy-2,4-iminoribonic acid is the first chemical synthesis of unprotected 3-hydroxyazetidine carboxylic acids. The long-term stability of 3-hydroxyazetidine amides is established at acidic and neutral pH and implies their value as non-proteinogenic amino acid components of peptides, providing medicinal chemists with a new class of peptide isosteres. The structure of N,3-O-dibenzyl-2,4-dideoxy-2,4-imino-D-ribonic acid was established by X-ray crystallographic analysis. An N-methylazetidine amide derivative is a specific inhibitor of ß-hexosaminidases at the micromolar level, and is only the second example of potent inhibition of any glycosidase by an amide of a sugar amino acid related to an iminosugar.
Assuntos
Aminoácidos/química , Ácido Azetidinocarboxílico/química , Azetidinas/química , Amidas/química , Animais , Ácido Azetidinocarboxílico/síntese química , Ácido Azetidinocarboxílico/metabolismo , Azetidinas/síntese química , Azetidinas/metabolismo , Cristalografia por Raios X , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Hexosaminidases/antagonistas & inibidores , Hexosaminidases/metabolismo , Humanos , Imino Açúcares/química , Conformação Molecular , Ligação Proteica , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Ring closure of a 3,5-di-O-triflate derived from D-altrose with benzylamine allowed the formation of both monocyclic and bicyclic azetidine analogues of swainsonine.
Assuntos
Azetidinas/síntese química , Hexoses/química , Manitol/análogos & derivados , Polímeros/síntese química , Swainsonina/análogos & derivados , Swainsonina/síntese química , Azetidinas/química , Ciclização , Imino Furanoses/síntese química , Imino Furanoses/química , Manitol/síntese química , Manitol/química , Manosidases/antagonistas & inibidores , Estrutura Molecular , Polímeros/química , Sorbitol/análogos & derivados , Relação Estrutura-Atividade , Swainsonina/químicaRESUMO
The efficient scalable syntheses of 2-acetamido-1,2-dideoxy-D-galacto-nojirimycin (DGJNAc) and 2-acetamido-1,2-dideoxy-D-gluco-nojirimycin (DNJNAc) from D-glucuronolactone, as well as of their enantiomers from L-glucuronolactone, are reported. The evaluation of both enantiomers of DNJNAc and DGJNAc, along with their N-alkyl derivatives, as glycosidase inhibitors showed that DGJNAc and its N-alkyl derivatives were all inhibitors of α-GalNAcase but that none of the epimeric DNJNAc derivatives inhibited this enzyme. In contrast, both DGJNAc and DNJNAc, as well as their alkyl derivatives, were potent inhibitors of ß-GlcNAcases and ß-GalNAcases. Neither of the L-enantiomers showed any significant inhibition of any of the enzymes tested. Correlation of the in vitro inhibition with the cellular data, by using a free oligosaccharide analysis of the lysosomal enzyme inhibition, revealed the following structure-property relationship: hydrophobic side-chains preferentially promoted the intracellular access of iminosugars to those inhibitors with more-hydrophilic side-chain characteristics.
Assuntos
1-Desoxinojirimicina/análogos & derivados , Acetamidas/química , Acetamidas/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glucuronatos/química , Hexosaminidases/antagonistas & inibidores , Hexosaminidases/química , Imino Piranoses/química , Oligossacarídeos/química , 1-Desoxinojirimicina/síntese química , 1-Desoxinojirimicina/química , Alquilação , Interações Hidrofóbicas e Hidrofílicas , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
Although there are 32 6-azidoheptitols, there are only 16 homonojirimycin (HNJ) stereoisomers. Two epimeric azidoalditols derived from d-mannose allow the synthesis in water of eight stereoisomers of HNJ.
Assuntos
1-Desoxinojirimicina/análogos & derivados , Manose/química , 1-Desoxinojirimicina/síntese química , 1-Desoxinojirimicina/química , Euphorbiaceae/química , Estrutura Molecular , EstereoisomerismoRESUMO
Noeuromycin is a highly potent albeit unstable glycosidase inhibitor due to its hemiaminal function. While stable D-gluco-like analogs have been reported, no data are available for D-manno-like structures. A series of tri- and tetrahydroxylated seven-membered iminosugars displaying either a D-manno-or a L-gulo-like configuration, were synthesized from methyl α-D-mannopyranoside using a reductive amination-mediated ring expansion as the key step. Screening towards a range of commercial glycosidases demonstrated their potency as competitive glycosidase inhibitors while cellular assay showed selective albeit weak glycoprotein processing mannosidase inactivation.