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Gluco-azoles competitively inhibit glucosidases by transition-state mimicry and their ability to interact with catalytic acid residues in glucosidase active sites. We noted that no azole-type inhibitors described, to date, possess a protic nitrogen characteristic for 1H-imidazoles. Here, we present gluco-1H-imidazole, a glucoazole bearing a 1H-imidazole fused to a glucopyranose-configured cyclitol core, and three close analogues as new glucosidase inhibitors. All compounds inhibit human retaining β-glucosidase, GBA1, with the most potent ones inhibiting this enzyme (deficient in Gaucher disease) on a par with glucoimidazole. None inhibit glucosylceramide synthase, cytosolic β-glucosidase GBA2 or α-glucosidase GAA. Structural, physical and computational studies provide first insights into the binding mode of this conceptually new class of retaining β-glucosidase inhibitors. [ABSTRACT FROM AUTHOR]

The excessive consumption of starch in human diets is associated with highly prevalent chronic metabolic diseases such as type 2 diabetes and obesity. α-Glucosidase enzymes contribute to the digestion of starch into glucose and are thus attractive therapeutic targets for diabetes. Given that the active sites of the various families of α-glucosidases have different sizes and structural features, atomistic descriptions of the catalytic mechanisms of these enzymes can support the development of potent and selective new inhibitors. Maltase-glucoamylase (MGAM), in particular, has a N-terminal catalytic domain (NtMGAM) that has shown high inhibitor selectivity. We provide here the first theoretical study of the human NtMGAM catalytic domain, employing a hybrid QM/MM approach with the ONIOM method to disclose the full atomistic details of the reactions promoted by this domain. We observed that the catalytic activity follows the classical Koshland double-displacement mechanistic pathway that uses general acid and base catalysts. A covalent glycosyl-enzyme intermediate was formed and hydrolyzed in the first and second mechanistic steps, respectively, through oxocarbenium ion-like transition state structures. The overall reaction is of dissociative type. Both transition state geometries differ from those known to occur in other glycosidases. The activation free energy for the glycosylation rate-limiting step agrees with the experimental barrier of 15.8 kcal·mol-1. Both individual mechanistic steps of the reaction are exoergonic. These structural results may serve as the basis for the design of transition state analogue inhibitors that specifically target the intestinal NtMGAM catalytic domain, thus delaying the production of glucose in diabetic and obese patients. [ABSTRACT FROM AUTHOR]

The highly stereocontrolled de novo synthesis of l-NBDNJ (the unnatural enantiomer of the iminosugar drug Miglustat) and a preliminary evaluation of its chaperoning potential are herein reported. l-NBDNJ is able to enhance lysosomal α-glucosidase levels in Pompe disease fibroblasts, either when administered singularly or when coincubated with the recombinant human α-glucosidase. In addition, differently from its d-enantiomer, l-NBDNJ does not act as a glycosidase inhibitor. [ABSTRACT FROM AUTHOR]

A facile and highly diastereoselective route to potent natural a-glucosidase inhibitors, i.e., neosalacinol (4) and neoponkoranol (6), isolated from the traditional Ayurvedic medicine "Salacia" was developed by intramolecular cyclization of appropriately substituted sulfides (9 and 12). [ABSTRACT FROM AUTHOR]

α,α-Disubstituted piperidinesand conformationallyconstrained polyhydroxylated indolizidines bearing a hydroxymethylsubstituent in position 8a were synthesized from a readily available l-sorbose-derived ketonitrone. Diastereoselective vinylationunder two sets of complementary conditions allowed access to bothconfigurations of the newly formed quaternary stereocenter. Subsequent N-allylation and ring-closing metathesis afforded 8a-branchedindolizidines in high yield. The newly prepared iminosugars demonstratedhighly potent inhibition of α-glucosidases. Most interestingly,compound 9bexhibits very high selectivity toward thisclass of enzymes, with an unusual mode of binding. [ABSTRACT FROM AUTHOR]

A formal synthesis of (-)-schulzeine B, a marine natural alkaloid possessing potent antidiabetic activity, has been achieved. A benzo[a]quinolizidin-4-one is a common skeleton of schulzeines (A-C). (-)-Schulzeine B possesses an (S)-stereogenic center at the C-3 carbon. The chiral (3S,11bS)-3-amino-9,11-dimethoxybenzo[a]quinolizidin-4-one has been prepared efficiently from (2-bromo-3,5-dihydroxyphenyl)acetonitrile in 17 steps including (i) a dehydrative intramolecular amination catalyzed by HClO4 and (ii) a proline or boric acid catalyzed transcycloamidation reaction for the construction of the δ-lactam ring. [ABSTRACT FROM AUTHOR]

In humans, four different enzymes mediate the digestion of ingested carbohydrates. First salivary and pancreatic α-amylases, the two endoacting retaining glucosidases, break down the complex starch molecules into smaller linear maltose-oligomers (LM) and branched α-limit dextrins (αLDx). Then two retaining exoglucosidases, maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI), convert those molecules into glucose in the small intestine. The small intestinal brush-border epithelial cells anchor MGAM and SI, and each contains a catalytic N- and C-terminal subunit, ntMGAM, ctMGAM, ntSI, and ctSI, respectively. All four catalytic domains have, to varying extents, α-1,4-exohydrolytic glucosidase activity and belong to the glycoside hydrolase family 31 (GH31). ntSI and ctSI show additional activity toward α-1,6 (isomaltose substrates) and α-1,2 (sucrose) glycosidic linkages, respectively. Because they mediate the final steps of starch digestion, both MGAM and SI are important target enzymes for the treatment of type-2 diabetes. [ABSTRACT FROM AUTHOR]

Newly emerged xanthone derivativeshave attracted considerableinterests as a novel class of potent α-glucosidase inhibitors.To provide insights into the inhibitory and binding mechanisms ofxanthone-based inhibitors toward α-glucosidase, we carried outexperimental and theoretical studies on two typical xanthone derivatives,i.e., 1,3,7-trihydroxyxanthone and 1,3-dihydroxybenzoxanthone. Theresults indicate that these two xanthone derivatives belong to noncompetitiveinhibitors and induce a loss in the α-helix content of the secondarystructure of α-glucosidase. Docking simulation revealed theexistence of multiple binding modes, in which polyhydroxyl groupsand expanded aromatic rings acted as two key pharmacophores to formH-bonding and π–π stacking interactions with α-glucosidase.The fact that 1,3,7-tridroxyxanthone and 1,3-dihydroxybenzoxanthoneexhibited significant synergetic inhibition to α-glucosidasestrongly suggests that both xanthone derivatives simultaneously bindto the distinct noncompetitive sites of yeast’s α-glucosidase.On the basis of the plausible binding clues, synergetic inhibitioncan be developed to be a promising strategy to achieve enhanced inhibitoryactivities. [ABSTRACT FROM AUTHOR]

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 [Ki 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. [ABSTRACT FROM AUTHOR]

We report on the synthesis and the biological evaluationof a series of ?-1-C-alkylated 1,4-dideoxy-1,4-imino-l-arabinitol (LAB) derivatives. The asymmetric synthesis ofthe derivatives was achieved by asymmetric allylic alkylation, ring-closingmetathesis, and Negishi cross-coupling as key reactions. ?-1-C-Butyl-LAB is a potent inhibitor of intestinal maltase,isomaltase, and sucrase, with IC50values of 0.13, 4.7,and 0.032 ?M, respectively. Matrix-assisted laser desorptionionization time-of-flight mass spectrometric analysis revealed thatthis compound differs from miglitol in that it does not influenceoligosaccharide processing and the maturation of glycoproteins. Amolecular docking study of maltase-glucoamylase suggested that theinteraction modes and the orientations of ?-1-C-butyl-LAB and miglitol are clearly different. Furthermore, ?-1-C-butyl-LAB strongly suppressed postprandial hyperglycemiaat an early phase, similar to miglitol in vivo. It is noteworthy thatthe effective dose was about 10-fold lower than that for miglitol.?-1-C-Butyl-LAB therefore represents a newclass of promising compounds that can improve postprandial hyperglycemia. [ABSTRACT FROM AUTHOR]

A series of conformationally locked N-glycosideshaving a cis-1,2-fused pyranose–1,3-oxazoline-2-thione structureand bearing different substituents at the exocyclic sulfur has beenprepared. The polyhydroxylated bicyclic system was built in only threesteps by treatment of the corresponding readily available 1,2-anhydrosugarwith KSCN using TiO(TFA)2as catalyst, followed by S-alkylationand acetyl deprotection. In vitro screening against several glycosidaseenzymes showed highly specific inhibition of mammalian β-glucosidasewith a marked dependence of the potency upon the nature of the exocyclicsubstituent. The most potent representative, bearing an S-(ω-hydroxyhexadecyl) substituent, was further assayed as inhibitorof the human lysosomal β-glucocerebrosidase and as pharmacologicalchaperone in Gaucher disease fibroblasts. Activity enhancements inN370S/N370S mutants analogous to those achieved with the referencecompound ambroxol were attained with a more favorable chaperone/inhibitorbalance. [ABSTRACT FROM AUTHOR]

Canarene (1), a triterpene with an unprecedented carbon backbone, was isolated from Canarium schweinfurthii. It is the first member of a new class of triterpenoids, for which the name “canarane’’ is proposed. 1showed weak α-glucosidase inhibitory activity, and its structure was unambiguously deduced by single-crystal X-ray diffraction. [ABSTRACT FROM AUTHOR]

Duboscic acid (1), a triterpenoid with a unique carbon backbone, was isolated from Duboscia macrocarpaBocq. It is the first member of a new class of triterpenoids, for which the name “dubosane” is proposed. Duboscic acid has a potent α-glucosidase inhibition, and its structure was unambiguously deduced by a single-crystal X-ray diffraction study. [ABSTRACT FROM AUTHOR]

A simple and reproducible capillazy-zone electrophoresis (CZE) method was developed for the separation and quantitalion of sulfonium-ion-containing compounds isolated from plants of the Salacia genus which are traditionally used in A urvedic medicine for the treatment of type-2 diabetes. The method sufficiently resolved four different compounds with confirmed glucosidase inhibitoiy activity, namely, salacinol, ponkoranol, kotalanol and de-O-sulfonated kotalanol. Separation could be achieved in less than 9 mm, and calibration curves showed good linearity. Detection limits were determined to be in the low pg/mL range. This method was used to demonstrate that de-Osulfonated kotalanol isolated from natural sources has identical ionic mobility to a synthetic standard. Furthermore, new extraction conditions were developed by which the zwitterionic compounds (salacinol, ponkoranol, and kotalanol) could be separated from de-O-sulfonated 1wtalanol in a single solid-phase extraction (SPE) procedure. The extraction gave reproducibly high recoveries and was used to process four commercial Salacia extracts for CZE analysis to reduce the complexity of resulting electropherograms and to facilitate the detection of the four inhibitors in question. De-O-sulfonated kotalanol was detected in two of four Salacia samples while ponkoranol was present in all four. A comparison of all samples tested demonstrated that they had remarkably similar patterns of peaks, suggesting that this CZE method may be useful in the chemical fingerprinting of Salacia-containing products. [ABSTRACT FROM AUTHOR]

An approach to controlling blood glucose levels in individuals with type 2 diabetes is to target α-amylases and intestinal glucosidases using α-glucosidase inhibitors acarbose and miglitol. One of the intestinal glucosidases targeted is the N-terminal catalytic domain of maltase-glucotsmylase (ntMGAM), one of the four intestinal glycoside hydrolase 31 enzyme activities responsible for the hydrolysis of terminal starch products into glucose. Here we present the X-ray crystallographic studies of ntMGAM in complex with a new class of α-glucosidase inhibitors derived from natural extracts of Salacia reticulata, a plant used traditionally in Ayuverdic medicine for the treatment of type 2 diabetes. Included in these extracts are the active compounds salacinol, kotalanol, and de-O-sulfonated kotalanol, This study reveals that de-O-sulfonttted kotalanol is the most potent ntMGAM inhibitor reported to date (Ki = 0.03 μM), some 2000-fold better than the compounds currently used in the clinic, and highlights the potential of the salacinol class of inhibitors as future drug candidates. [ABSTRACT FROM AUTHOR]

In vitro α-glucosidase inhibition assays and ultrafiltration liquid chromatography with photodiode array detection coupled to electrospray ionization tandem mass spectrometry (ultrafiltration LC-DAD-ESI-MS) were combined to screen α-glucosidase inhibitors from hawthorn leaf flavonoids extract (HLFE). As a result, four compounds were identified as α-glucosidase inhibitors in the HLFE, and their structures were confirmed to be quercetin-3-O-rha- (1-4)-glc-rha and C-glycosylflavones (vitexin-2″-O-glucoside, vitexin-2″-O-rhamnoside and vitexin) by high-resolution sustained off resonance irradiation collision-induced dissociation (SORI-CID) data obtained by Fourier transform ion cyclotron resonance mass spectrometry (FTICR MS). Several other C-glycosylflavones (vitexin, isovitexin, orientin, isooriention) and their aglycones apigenin and luteolin were evaluated by in vitro assays, and were found to possess strong α-glucosidase inhibitory activities as well. Moreover, the substituent groups on the flavones had a great impact on the enzyme inhibition activity. C-3′-OH of the B-ring of flavones in particular increased the α-glucosidase inhibition activity, whereas C-glycosylations at C-6 or C-8 of the A ring weakened the inhibition activity. [ABSTRACT FROM AUTHOR]

Enantioselective syntheses of the glucosidase inhibitors schulzeines B and C were achieved by employing a Pictet−Spengler reaction of a β-lactone-derived, masked bishomoserine aldehyde. Subsequent Corey−Link reaction unveiled an α-azido acid enabling cyclization to the δ-lactam fused tetrahydroisoquinoline. An efficient synthesis of the trisulfate-bearing side chain featured a Noyori hydrogenation and a Sharpless dihydroxylation. An unexpected reaction of a pendant amine during a Corey−Link process opens avenues for the synthesis of proline and related amino acid derivatives. [ABSTRACT FROM AUTHOR]

The expeditious synthesis of a common intermediate of L-1- deoxyallonojirimycin (L-allo-DNJ) and L- 1 -deoxymannojiri-mycin (L-manno-DNJ) is reported. This intermediate is obtained in highly diastereo- and enantioselectivity with 38.4% overall yield in six steps involving the unprecedented ring-closing metathesis of a tert-butylsulfinyl allylamine as the key step. [ABSTRACT FROM AUTHOR]

α-Glucosidases play important roles in the digestion of carbohydrates and biosynthesis of viral envelope glycoproteins. Inhibitors of α-glucosidase are promising candidates for the development of antitype II diabetics and anti-AIDS drugs. Here, we report the synthesis and α-glucosidase inhibitory activity of mono- and diketal/acetal derivatives of chlorogenic acid. The diketal derivatives showed more potent inhibitory activity than the monoketals. The 1,7-(5-nonanone) 3,4-(5-nonanone)-chlorogenic acid diketal showed remarkable inhibitory activity against α-glucosidases with potency better than that of 1-deoxynojirimycin hydrochloride. Four diasteremers of pelargonaldehyde diacetal and two of monoacetal derivatives of chlorogenic acid were synthesized in this study. They showed significant potent inhibition similar to or more potent than the ketal counterparts. Acetals with the alkyl chain oriented toward position 2 of chlorogenic acid showed more potent activity than those oriented toward position 6. [ABSTRACT FROM AUTHOR]

Six chain-extended analogues of the naturally occurring glycosidase inhibitor salacinol, with ring-heteroatom variation, were synthesized for structure-activity studies with different glycosidase enzymes. The syntheses involved the reaction of PMB-protected ᴅ- and ʟ- seleno-, thio-, and iminoarabinitol with a benzylidene- and isopropylidene-protected 1,3-cyclic sulfate, derived from commercially available ᴅ-sorbitol, in 1,1,1,3,3,3-hexafluoro-2-propanol containing potassium carbonate. Deprotection of the products afforded the novel selenonium, sulfonium, and iminium analogues of salacinol containing polyhydroxylated, monosulfated, extended acyclic chains of 6-carbons, differing in stereochemistry at the stereogenic centers and ring-heteroatom constitution. Four of these compounds inhibit recombinant human maltase glucoamylase, one of the key intestinal enzymes involved in the breakdown of glucose oligosaccharides in the small intestine, with Ki values in the micromolar range, thus providing lead candidates for the treatment of Type 2 diabetes. [ABSTRACT FROM AUTHOR]

A new synthesis of (+)-cyclophellitol, a potent β-glucosidase inhibitor, has been completed in nine steps from D-xylose. The key transformations involve a zinc-mediated fragmentation of benzyl-protected methyl 5-deoxy-5-iodo-xylofuranoside followed by a highly diastereoselective indium-mediated coupling with ethyl 4-bromocrotonate. Subsequent ring-closing olefin metathesis, ester reduction, olefin epoxidation, and deprotection then afford the natural product. This constitutes the shortest synthesis of (+)-cyclophellitol reported to date. [ABSTRACT FROM AUTHOR]

Three new α-glucosidase inhibitors, schuizeines A-C (1-3), were isolated from the marine sponge Penares schulzei. Their structures were elucidated by spectral analysis and chemical degradations to be the isoquinoline alkaloids, encompassing two amino acids, and C[SUB28] fatty acid, the last of which was sulfated. Absolute stereochemistry of schuizeines was determined by application of the modified Mosher analysis to fragments obtained by chemical degradation. Schuizeines A-C inhibit α-glucosidase with IC[SUB50] values of 48-170 nM. [ABSTRACT FROM AUTHOR]

Examines the properties and production of valienamine and its related pseudo-sugars. Degradation of validoxylamine A with Flavobacterium saccharophilum; Role of glycosidases in glycoprotein processing; Chemical structures of various pseudo-aminosugar glucose inhibitors.

Describes the synthesis of Valienamine, an alpha-glucosidase inhibitor. Isolation of the compound from the microbial degradation of validoxylamine A; Determination of the 2-epi-valienamine derivative; Production of valienamine from a cyclohexene precursor bearing an allylic acetate moiety.

Examines the use of hydrolated indolizidines as a potent inhibitors of glucosidase for cancer therapy. Synthesis of epilentiginosine and lentiginosine; Preparation of indolizidines; Inhibition of fungal alpha-glucosidase amyloglucosidase.

Reports on the synthesis of enantiopure di- and tetrahydroxyindolizidines from stereoisomeric sugar-derived indolizines. Selective inhibitor of amyloglucosidase; Catalytic hydrogenation of indolizine; Contributing factors that add versatility to the chiral building blocks; Catalytic cycle reactivation by acetic acid.

Focuses on the synthesis of a series of aminoketalic castanospermine analogues with a stereoelectronically anchored axial hydroxy group at the pseudoanomeric stereocenter to satisfy the need for glucosidase inhibitors that are highly selective for alpha-glucosidases. Development of the polyhydroxylated bicyclic system.

Presents information on a study on the alpha-glucosidase inhibitor acarbose in Actinoplanes sp. strain SN 223/29. Biosynthesis of the deoxysugar moiety of acarbose; Feeding experiments with tritiated precursors; Experiments with 1-epi-Valienol; Experimental section.

Discusses inhibition of alpha-glucosidases and glycoprotein processing glucosidase by castanospermine. Measurement of surface binding; Effect of castanospermine on the composition of oligosaccharides; Influence of pretreatment of BAEC with increasing castanospermine concentrations; Effects of different glycoprotein processing inhibitor.

Reports a flexible enantiodivergent synthesis of analogues that exhibit glucosidase inhibition. Biological activity of mannostatin analogues; Enantiodivergent route to the desired compounds starting from (S)-4-((tert-butyldimethyl)oxy)-2-cyclopentenone; Cyclitol glycosidase inhibitors; Suggested directions for further research.

Provides information on a study using the novel bromoketon C-glycoside inactivator to label the putative acid/base catalyst (Glu-276) of yeast ...-glucosidase. Methodology used to conduct the study; Results of the study; Discussion on the results.

The article describes a synthetic method for planar catechin analogues, the lipophilicity of which was controlled by changing the length of the alkyl chains. The synthesis was conducted by reacting catechin with various ketones having alkyl chains of different lengths. The reaction was optimized using a combination of various acids and solvents. The compounds show remarkable properties as potent antioxidants and α-glucosidase inhibitors.

Focuses on 5-fluro glycosides, a new class of mechanism-based inhibitors of both alpha- and beta-glucosidases. Role of glycosidase inhibitors as probes of enzymic mechanism; Design of inhibitors; Synthesis of the 5-fluoroglycosyl fluorides.

Describes the synthesis of the (1-->4)-linked `trehazoloid' analogous to trehazolin, an alpha,alpha-trehalase inhibitor. Synthesis of the trehazolin aminocyclitol portion; Competitive inhibition of yeast alpha-glucosidase by trehazoloid; Selectivity due to aglycon portion.