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Glycosidase Inhibitors (glycosidase + inhibitor)
Selected AbstractsSynthesis of Hybrids of D -Glucose and D -Galactose with Pyrrolidine-Based Iminosugars as Glycosidase InhibitorsEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 34 2008Venkata Ramana Doddi Abstract Sugar,iminosugar hybrid molecules made up of D -glucose and D -galactose with pyrrolidine-based iminosugars, viz. 1,4-dideoxy-1,4-imino- L -xylitol and 1,4-dideoxy-1,4-imino- L -lyxitol, are synthesized from glycal epoxides and found to be moderate glycosidase inhibitors. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008) [source] Synthetic Routes to Three Novel Scaffolds for Potential Glycosidase InhibitorsEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 26 2007Michael Rommel Abstract Efficient syntheses of three novel scaffolds for potential ,-glycosidase inhibitors were developed: The first consists of a 2,7-dioxabicyclo[2.2.1]heptane derivative, which was prepared by an intramolecular ketalisation. The second scaffold consists of a hydroxylated cyclopentylamine, which could be synthesised stereoselectively from 2-azabicyclo[2.2.1]hept-5-en-3-one. The third scaffold, a 4,5-dihydroxynicotinic acid, was accessible through a sequence of substituent directed ortho -lithiations. Selected compounds were tested as inhibitors for a number of glycosidases. Three nicotinic acid derivatives were found to be selective ,-glucosidase inhibitors.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) [source] Synthesis of 2-Azabicyclo[3.2.2]nonane-Derived Monosaccharide Mimics and Their Evaluation as Glycosidase InhibitorsHELVETICA CHIMICA ACTA, Issue 3 2006Stephan Buser Abstract The racemic 2-azabicyclo[3.2.2]nonanes 5 and 18 were synthesized and tested as , -glycosidase inhibitors. The intramolecular Diels,Alder reaction of the masked o -benzoquinone generated from 2-(allyloxy)phenol (6) gave the , -keto acetal 7 which was reduced with SmI2 to the hydroxy ketone 8. Dihydroxylation, isopropylidenation (,,12), and Beckmann rearrangement provided lactam 15. N -Benzylation of this lactam, reduction to the amine 17, and deprotection provided the amino triol 19 which was debenzylated to the secondary amine 5. Both 5 and 19 proved weak inhibitors of snail , -mannosidase (IC50,>,10,mM), Caldocellum saccharolyticum , -glucosidase (IC50,>,10,mM), sweet almond , -glucosidase (IC50,>,10,mM), yeast , -glucosidase (5: IC50,>,10,mM; 19: IC50,=,1.2,mM), and Jack bean , -mannosidase (no inhibition detected). [source] Synthesis of N -Acetylglucosamine-Derived Nagstatin Analogues and Their Evaluation as Glycosidase InhibitorsHELVETICA CHIMICA ACTA, Issue 1 2005Miroslav Terinek The gluco -configured analogue 15 of nagstatin (1) and the methyl ester 14 were synthesized via condensation of the thionolactams 17 or 18 with the , -amino ester 19. The silyl ethers 20 and 21 resulting from 17 were desilylated to 22 and 23; these alcohols were directly obtained by condensing 18 and 19. The attempted substitution of the C(8)OH group of 22 by azide under Mitsunobu conditions led unexpectedly to the deoxygenated , -azido esters 24. The desired azide 25 was obtained by treating the manno -configured alcohol 23 with diphenyl phosphorazidate. The azide was transformed to the debenzylated acetamido ester 14 that was hydrolyzed to the nagstatin analogue 15. The imidazole-2-acetates 14 and 15 are nanomolar inhibitors of the N -acetyl- , -glucosaminidases from Jack beans and from bovine kidney, submicromolar to micromolar inhibitors of the , -glucosidase from Caldocellum saccharolyticum, and rather weak inhibitors of the snail , -mannosidase. In all cases, the ester was a stronger inhibitor than the corresponding acid. As expected from their gluco -configuration, both imidazopyridines 14 and 15 are stronger inhibitors of the , - N -acetylglucosaminidase from bovine kidney than nagstatin. [source] Synthesis of N -Substituted (3S,4S)- and (3R,4R)-Pyrrolidine-3,4-diols: Search for New Glycosidase InhibitorsHELVETICA CHIMICA ACTA, Issue 12 2004Robert N -Substituted (3S,4S)- and (3R,4R)-pyrrolidine-3,4-diols 9 and 10, respectively, were derived from (+)- L - and (,)- D -tartaric acid, respectively. Compounds 9k, 9l, and 9m with the N -substituents, BnNH(CH2)2, 4-PhC6H4CH2NH(CH2)2 and 4-ClC6H4CH2NH(CH2)2, respectively, showed modest inhibitory activities toward , - D -amyloglucosidases from Aspergillus niger and from Rhizopus mold (Table,1). Unexpectedly, several (3R,4R)-pyrrolidine-3,4-diols 10 showed inhibitory activities toward , - D -mannosidases from almonds and from jack bean (Table,3). N -Substitution by the NH2(CH2)2 group, i.e., 10g, led to the highest potency. [source] Synthesis of Monosaccharide-Derived Spirocyclic Cyclopropylamines and Their Evaluation as Glycosidase InhibitorsHELVETICA CHIMICA ACTA, Issue 9 2003Christian Blüchel The glucose-, mannose-, and galactose-derived spirocyclic cyclopropylammonium chlorides 1a,1d, 2a,2d and 3a,3d were prepared as potential glycosidase inhibitors. Cyclopropanation of the diazirine 5 with ethyl acrylate led in 71% yield to a 4,:,5,:,1,:,20 mixture of the ethyl cyclopropanecarboxylates 7a,7d, while the Cu-catalysed cycloaddition of ethyl diazoacetate to the exo -glycal 6 afforded 7a,7d (6,:,2,:,5,:,3) in 93,98% yield (Scheme,1). Saponification, Curtius degradation, and subsequent addition of BnOH or t- BuOH led in 60,80% overall yield to the Z- or Boc-carbamates 11a,11d and 12a,12d, respectively. Hydrogenolysis of 11a,11d afforded 1a,1d, while 12a,12d was debenzylated to 13a,13d prior to acidic cleavage of the N -Boc group. The manno - and galacto -isomers 2a,2d and 3a,3d, respectively, were similarly obtained in comparable yields (Schemes,2 and 4). Also prepared were the differentially protected manno- configured esters 24a,24d; they are intermediates for the synthesis of analogous N -acetylglucosamine-derived cyclopropanes (Scheme,3). The cyclopropylammonium chlorides 1a,1d, 2a,2d and 3a,3d are very weak inhibitors of several glycosidases (Tables,1 and 2). Traces of Pd compounds, however, generated upon catalytic debenzylation, proved to be strong inhibitors. PdCl is, indeed, a reversible, micromolar inhibitor for the ,- glucosidases from C. saccharolyticum and sweet almonds (non-competitive), the , -galactosidases from bovine liver and from E. coli (both non-competitive), the , -galactosidase from Aspergillus niger (competitive), and an irreversible inhibitor of the , -glucosidase from yeast and the , -galactosidase from coffee beans. The cyclopropylamines derived from 1a,1d or 3a,3d significantly enhance the inhibition of the ,- glucosidase from C. saccharolyticum by PdCl, lowering the Ki value from 40,,M (PdCl) to 0.5,,M for a 1,:,1 mixture of PdCl and 1d. A similar effect is shown by cyclopropylamine, but not by several other amines. [source] Synthesis and Comparative Glycosidase Inhibitory Properties of Reducing Castanospermine AnaloguesEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 14 2005Paula Díaz Pérez Abstract The feasibility of the intramolecular nucleophilic addition of the nitrogen atom in cyclic (thio)carbamates with a pseudo- C -nucleoside structure to the masked carbonyl group in aldose precursors in the synthesis of reducing (i.e., 5-hydroxy)6-oxaindolizidine frameworks is illustrated by the preparation of the 6- epi, 7- epi, 8- epi and 6,8a-di- epi diastereomers of the potent glycosidase inhibitor (+)-castanospermine. In all cases, the increased anomeric effect caused by the high sp2 character of the pseudoamide-type nitrogen atom resulted in the pseudoanomeric hydroxy group being anchored in an axial orientation in aqueous solution, as in the aglycons in ,-glycosides. These analogs of the natural alkaloid showed a higher selectivity in the inhibition of ,-glucosidases. Structure/glycosidase inhibitory activity studies indicated that inversion of any hydroxy group resulted in a dramatic decrease in the inhibition potency, confirming the critical importance of a correct hydroxylation profile. In the case of (+)-8- epi -6-oxacastanospermine derivatives, with a hydroxylation profile with a structural complementarity to that of D -galactose, a moderate but very selective inhibition of ,-galactosidase was observed, supporting the importance of a defined configuration at pseudoanomeric centres for anomeric specificity. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005) [source] Synthesis and Glycosidase Inhibitory Study of New Polyhydroxylated IndolizidinesEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 31 2008Delphine Baumann Abstract The synthesis of two polyhydroxylated indolizidines as potenticial glycosidase inhibitors is reported. The piperidine ring was formed by an intramolecular Mannich-type reaction between ethyl trans -4-oxo-2-butenoate and the two ,-amino ketones (,)-1-(2-methyl-1,3-dioxan-2-yl)propan-2-amine and(+)-1-(benzyloxymethyl)-2-(2-methyl-1,3-dioxan-2-yl)ethylamine. The synthesis of this amine was performed in eight steps from L -aspartic acid. The key steps of the formation of the framework involved dihydroxylation, nucleophilic substitution, and reduction. The last hydroxy group was introduced by hydrolysis of the acetal moiety followed by reduction of the resulting ketone. The inhibitory properties of the two synthesized indolizidines were evaluated against a variety of commercial glycosidases. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008) [source] Synthetic Routes to Three Novel Scaffolds for Potential Glycosidase InhibitorsEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 26 2007Michael Rommel Abstract Efficient syntheses of three novel scaffolds for potential ,-glycosidase inhibitors were developed: The first consists of a 2,7-dioxabicyclo[2.2.1]heptane derivative, which was prepared by an intramolecular ketalisation. The second scaffold consists of a hydroxylated cyclopentylamine, which could be synthesised stereoselectively from 2-azabicyclo[2.2.1]hept-5-en-3-one. The third scaffold, a 4,5-dihydroxynicotinic acid, was accessible through a sequence of substituent directed ortho -lithiations. Selected compounds were tested as inhibitors for a number of glycosidases. Three nicotinic acid derivatives were found to be selective ,-glucosidase inhibitors.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007) [source] On the Way to Glycoprocessing Inhibitors , Synthesis of an Imidazolo-Nectrisine-Phosphono Acid Derivative: A Potential Glycosyltranferase InhibitorEUROPEAN JOURNAL OF ORGANIC CHEMISTRY, Issue 15 2003Théophile Tschamber Abstract Assuming the transition state of glycosyltransferase inhibitors to be similar to those encountered with potent glycosidase inhibitors , i.e. a flattened conformation with a positively charged anomeric centre , we worked out a synthesis of the D - arabino -configured phosphonic acid target molecule 2 derived from an imidazolo-sugar. The key synthetic intermediate is the linear imidazolo L - xylo compound 10 which could be obtained, either from L - threo precursor 6 by a coupling reaction with imidazole derivative 5, or from L -sorbose. A multi-step and site specific iodination of 10 gave the mono-iodo- L - xylo derivative 14 which was cyclised to the D - arabino -configured bicyclic azasugar 15. Phosphorylation of the Grignard derivative of the latter, followed by mono-esterification with citronellol along with some protection-deprotection steps led to target molecule 2. The potential inhibitor 2 is supposed to be protonated at its most basic N atom by a carboxylic acid residue in the arabinosyl-transferase active site. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003) [source] Differential mechanism-based labeling and unequivocal activity assignment of the two active sites of intestinal lactase/phlorizin hydrolaseFEBS JOURNAL, Issue 24 2000Juan C. Díaz Arribas Milk lactose is hydrolysed to galactose and glucose in the small intestine of mammals by the lactase/phlorizin hydrolase complex (LPH; EC 3.2.1.108/62). The two enzymatic activities, lactase and phlorizin hydrolase, are located in the same polypeptide chain. According to sequence homology, mature LPH contains two different regions (III and IV), each of them homologous to family 1 glycosidases and each with a putative active site. There has been some discrepancy with regard to the assignment of enzymatic activity to the two active sites. Here we show differential reactivity of the two active sites with mechanism-based glycosidase inhibitors. When LPH is treated with 2,,4,-dinitrophenyl 2-deoxy-2-fluoro-,- d -glucopyranoside (1) and 2,,4,-dinitrophenyl-2-deoxy-2-fluoro-,- d -galactopyranoside (2), known mechanism-based inhibitors of glycosidases, it is observed that compound 1 preferentially inactivates the phlorizin hydrolase activity whereas compound 2 is selective for the lactase active site. On the other hand, glycals (d -glucal and d -galactal) competitively inhibit lactase activity but not phlorizin hydrolase activity. This allows labeling of the phlorizin site with compound 1 by protection with a glycal. By differential labeling of each active site using 1 and 2 followed by proteolysis and MS analysis of the labeled fragments, we confirm that the phlorizin hydrolysis occurs mainly at the active site located at region III of LPH and that the active site located at region IV is responsible for the lactase activity. This assignment is coincident with that proposed from the results of recent active-site mutagenesis studies [Zecca, L., Mesonero, J.E., Stutz, A., Poiree, J.C., Giudicelli, J., Cursio, R., Gloor, S.M. & Semenza, G. (1998) FEBS Lett.435, 225,228] and opposite to that based on data from early affinity labeling with conduritol B epoxide [Wacker, W., Keller, P., Falchetto, R., Legler, G. & Semenza, G. (1992) J. Biol. Chem.267, 18744,18752]. [source] Synthesis of 2-Azabicyclo[3.2.2]nonane-Derived Monosaccharide Mimics and Their Evaluation as Glycosidase InhibitorsHELVETICA CHIMICA ACTA, Issue 3 2006Stephan Buser Abstract The racemic 2-azabicyclo[3.2.2]nonanes 5 and 18 were synthesized and tested as , -glycosidase inhibitors. The intramolecular Diels,Alder reaction of the masked o -benzoquinone generated from 2-(allyloxy)phenol (6) gave the , -keto acetal 7 which was reduced with SmI2 to the hydroxy ketone 8. Dihydroxylation, isopropylidenation (,,12), and Beckmann rearrangement provided lactam 15. N -Benzylation of this lactam, reduction to the amine 17, and deprotection provided the amino triol 19 which was debenzylated to the secondary amine 5. Both 5 and 19 proved weak inhibitors of snail , -mannosidase (IC50,>,10,mM), Caldocellum saccharolyticum , -glucosidase (IC50,>,10,mM), sweet almond , -glucosidase (IC50,>,10,mM), yeast , -glucosidase (5: IC50,>,10,mM; 19: IC50,=,1.2,mM), and Jack bean , -mannosidase (no inhibition detected). [source] Synthesis of Monosaccharide-Derived Spirocyclic Cyclopropylamines and Their Evaluation as Glycosidase InhibitorsHELVETICA CHIMICA ACTA, Issue 9 2003Christian Blüchel The glucose-, mannose-, and galactose-derived spirocyclic cyclopropylammonium chlorides 1a,1d, 2a,2d and 3a,3d were prepared as potential glycosidase inhibitors. Cyclopropanation of the diazirine 5 with ethyl acrylate led in 71% yield to a 4,:,5,:,1,:,20 mixture of the ethyl cyclopropanecarboxylates 7a,7d, while the Cu-catalysed cycloaddition of ethyl diazoacetate to the exo -glycal 6 afforded 7a,7d (6,:,2,:,5,:,3) in 93,98% yield (Scheme,1). Saponification, Curtius degradation, and subsequent addition of BnOH or t- BuOH led in 60,80% overall yield to the Z- or Boc-carbamates 11a,11d and 12a,12d, respectively. Hydrogenolysis of 11a,11d afforded 1a,1d, while 12a,12d was debenzylated to 13a,13d prior to acidic cleavage of the N -Boc group. The manno - and galacto -isomers 2a,2d and 3a,3d, respectively, were similarly obtained in comparable yields (Schemes,2 and 4). Also prepared were the differentially protected manno- configured esters 24a,24d; they are intermediates for the synthesis of analogous N -acetylglucosamine-derived cyclopropanes (Scheme,3). The cyclopropylammonium chlorides 1a,1d, 2a,2d and 3a,3d are very weak inhibitors of several glycosidases (Tables,1 and 2). Traces of Pd compounds, however, generated upon catalytic debenzylation, proved to be strong inhibitors. PdCl is, indeed, a reversible, micromolar inhibitor for the ,- glucosidases from C. saccharolyticum and sweet almonds (non-competitive), the , -galactosidases from bovine liver and from E. coli (both non-competitive), the , -galactosidase from Aspergillus niger (competitive), and an irreversible inhibitor of the , -glucosidase from yeast and the , -galactosidase from coffee beans. The cyclopropylamines derived from 1a,1d or 3a,3d significantly enhance the inhibition of the ,- glucosidase from C. saccharolyticum by PdCl, lowering the Ki value from 40,,M (PdCl) to 0.5,,M for a 1,:,1 mixture of PdCl and 1d. A similar effect is shown by cyclopropylamine, but not by several other amines. [source] Calystegines in Calystegia sepium do not Inhibit Fungal Growth and Invertase Activity but Interact with Plant InvertasePLANT BIOLOGY, Issue 2 2004D. Höke Abstract: Calystegines are alkaloidal glycosidase inhibitors. They accumulate predominantly in young and meristemic parts of Calystegia sepium (Convolvulaceae). C. sepium, bindweed, infests meadows and cereal fields and is difficult to control chemically. Fungal pathogens against C. sepium are established as mycoherbicides. Stagonospora convolvuli LA39 attacks C. sepium and does not affect crop plants, but young plants of C. sepium are less susceptible to the fungus. The interaction of Stagonospora convolvuli with calystegines was investigated. Further, endophytic fungi of several classes were isolated from wild-grown Calystegia sepium leaves, and selected strains were tested for interaction with calystegines. Fungal growth on agar containing calystegines was not affected considerably. Plants in climate chambers were infected with an endophyte, Phomopsis, and with the fungal pathogen, Stagonospora convolvuli. Calystegine levels were measured in infected and non-infected plant tissues. Accumulation depended on developmental stage of the plant tissue and was not influenced by infection. Acid invertase was measured from fungal mycelia and from infected and non-infected plant tissues. Fungal acid invertase activity was not inhibited by 10 mM calystegine B2, while invertase from C. sepium leaves was inhibited. It is concluded that calystegines do not inhibit fungal development and sucrose consumption under the conditions of the present investigation, but may act by redirection of plant carbohydrate metabolism. [source] | ||||||||||