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The scope of a one-pot tandem approach for the synthesis of C-1 alkyl iminoalditol derivatives with a Staudinger/aza-Wittig/Grignard cascade has been evaluated. The reaction conditions have been optimized for two azidodeoxy aldose substrates and a range of Grignard reagents. The nature of both, substrate as well as nucleophile, was found to control the stereoselectivity of the alkyl addition to the cyclic iminium intermediate at position C-1. This approach enabled the synthesis of a collection of C -alkyl iminoalditols, which were biologically evaluated as inhibitors against a set of standard glycoside hydrolases. All compounds were found to exhibit highly selective inhibition of β-glucosidase activity. [ABSTRACT FROM AUTHOR]

Voglibose, an N -1,3-dihydroxypropylaminocyclitol, has widely been used as an effective α-glucosidase inhibitor for diabetes therapy. Several attempts have been made to synthesize closely related analogues through the coupling of various aminocyclitols and propane-1,3-diol; however, most of them showed weaker or no inhibition. In this communication, we synthesized a pair of new N -1,3-dihydroxypropylaminocyclitols ( 10 and 11 ) using (+)- proto -quercitol ( 1 ) as a cyclitol core structure. The newly synthesized compounds revealed potent rat intestinal α-glucosidases, particularly against maltase, with IC 50 values at submicromolar. Subsequent study on mechanisms underlying the inhibition of 11 indicated the competitive manner towards maltase and sucrase. The potent inhibition of these compounds was elaborated by docking study, in which their binding profiles towards key amino acid residues in the active site were similar to that of voglibose. Therefore, introduction of propane-1,3-diol moiety to suitable cyclohexane core structure such as aminoquercitol would be a potential approach to discover a new series of effective α-glucosidase inhibitors. [ABSTRACT FROM AUTHOR]

A series of compounds were synthesized by glycosylation of maslinic acid (MA) and corosolic acid (CA) with monosaccharides and disaccharides, and the structures of the derivatives were elucidated by standard spectroscopic methods including 1 H NMR, 13 C NMR and HRMS. The α-glucosidase inhibitory activities of all the novel compounds were evaluated in vitro . The solubility and inhibitory activity of α-glucosidase assays showed that the bis-disaccharide glycosides of triterpene acids possessed higher water solubility and α-glucosidase inhibitory activities than the bis-monosaccharide glycosides. Among these compounds, maslinic acid bis-lactoside (8e, IC 50  = 684 µM) and corosolic acid bis-lactoside (9e, IC 50  = 428 µM) had the best water solubility, and 9e exhibited a better inhibitory activity than acarbose (IC 50  = 478 µM). However, most of glycosylated derivatives possessed lower inhibitory activities than the parent compounds, although their water solubility was enhanced obviously. Moreover, the kinetic inhibition studies indicated that 9e was a non-competitive inhibitor, and structure–activity relationships of the derivatives are also discussed. [ABSTRACT FROM AUTHOR]

In human, digestion of cooked starch mainly involves breaking down of α-amylase to α-limit dextrins and small linear malto-oligosaccharides, which are in turn hydrolyzed to glucose by the gut mucosal maltase-glucoamylase (MGAM). Human pancreatic α-amylase (HPA), amino- and carboxyl-terminal portions of MGAM (ntMGAM and ctMGAM) catalyze the hydrolysis of α- d -(1,4) glycosidic linkages in starch, playing a crucial role in the production of glucose in the human lumen. Accordingly, these enzymes are effective drug targets for the treatments of type 2 diabetes and obesity. In this study, a Plackett–Burman based statistical screening procedure was adopted to determine the most critical factors affecting cooked starch digestion by the combination of HPA, ctMGAM and ntMGAM. Six factors were tested and experimental results showed that pH and temperature were the major influencing factors, with optimal pH and temperature at 6.0 and 50 °C, respectively. Surprisingly, ntMGAM had no significant contribution to the glucose production from starch digestion compared to the HPA and ctMGAM. The optimal proportion of HPA and ctMGAM in a starch digestion system was further determined by response surface methodology. Results showed a maximum starch digestion (88.05%) within 0.5 h when used HPA:ctMGAM=1:9 (U). The inhibitory effects of various inhibitors on the cooked starch digestion by HPA 1 /ctMGAM 9 were evaluated by determining their half maximal inhibitory concentration (IC 50 ) values. Acarviostatin II03 showed the highest inhibitory activity, with 67 times higher potency than acarbose. Moreover, acarviostatin II03 could significantly depress postprandial blood glucose levels in mice, better than that by acarbose. These findings suggest that our in vitro enzymatic system can simulate in vivo starch digestion process, and thus can be used to screen and evaluate α-glucosidase inhibitors. [ABSTRACT FROM AUTHOR]

In this study a novel series of poly-hydroxyl functionalized acridine derivatives ( L 1 – L 9 ) was synthesized and their inhibitory activities against α-Glucosidase (α-Gls) and α-Amylase (α-Amy) were evaluated, spectroscopically. The synthetic compounds consist of three different substructures, including a 4-(4-aminophenoxy) phenyl group (R 3 ), an acridine moiety (R 2 ) and a poly-hydroxy chain (R 1 ). The results indicate that among the synthetic compounds, L 5 with a chromeno[3′,4′:5,6]pyrido[2,3- d ]pyrimidine moiety demonstrates the highest inhibitory activity against both yeast and rat α-Gls enzymes. Also, L 2 with the thioxo-pyrido[2,3- d :6,5- d ′] dipyrimidine moiety plays an important role in the inhibition of yeast α-Gls. In addition, the results may suggest a significant role for the nature of sugar moiety of the synthetic compounds in their inhibitory action against α-Gls. Moreover, in comparison with Acarbose, which is a widely used anti -diabetic drug, these compounds show negligible inhibitory activity against pancreatic α-Amy, which is important in the term of their reduced susceptibility for possible development of the intestinal disturbance side effects. Results of this study may suggest these synthetic compounds as novel molecular templates for construction of potentially anti -diabetic drugs with the ability for more convenient management of postprandial hyperglycemia. [ABSTRACT FROM AUTHOR]

1- N -Carboxamide 1-azafagomines and 5- epi -1-azafagomines were obtained from 1-azafagomine and 5- epi -1-azafagomine. The hydroxyl groups and the N -2 pyridazine position were protected prior to reaction with different isocyanates to form ureas. Protective groups were removed leading to the target compounds in 18–23% global yields. Final compounds were tested towards α- and β-glucosidases. [ABSTRACT FROM AUTHOR]

Highlights: [•] Synthesis of new pyrimidine-fused heterocycles (PFH) as potent and selective α-Gls inhibitors. [•] The PFH ring plays an important role in the inhibitory activity of synthetic ligands. [•] The rigidity/flexibility of hinge-like connection is key in the inhibitory activity. [•] The synthesized ligands weakly inhibit the activity of pancreatic α-Amy. [Copyright &y& Elsevier]

Abstract: Ten new 1,2,3-triazole glycoconjugates were synthesized from d-glucose and evaluated in in vitro assays for their ability to inhibit the enzyme α-glucosidase. Most of the compounds had low activity or were inactive when compared with acarbose. However, the derivative 1,2-O-isopropylidene-3-phenyl-5-(4-phenyl-1H-1,2,3-triazole-1-yl)-α-d-ribofuranose (19i) possessed activity comparable with the standard drug. The influence of the phenyl group on carbon 3 of the carbohydrate framework is discussed. [Copyright &y& Elsevier]

Abstract: In humans, both the N-terminal catalytic domain (NtMGAM) and the C-terminal catalytic domain (CtMGAM) of small intestinal maltase glucoamylase (MGAM) are α-glycosidases that catalyze the hydrolysis of α-(1→4) glycosidic linkages in the process of starch digestion, and are considered to be the main therapeutic targets for type 2 diabetes. In this work, recombinant human CtMGAM has been cloned for the first time, and this, combined with the expression of NtMGAM in Pichia pastoris, made it possible for us to study the catalytic mechanism of MGAM in a well-defined system. The enzymatic kinetic assays of the two catalytic domains suggest that CtMGAM has the higher affinity for longer maltose oligosaccharides. Kinetic studies of commercially-available drugs such as 1-deoxynojirimycin (DNJ), miglitol, voglibose, and acarbose along with a series of acarviosine-containing oligosaccharides we isolated from Streptomyces coelicoflavus against NtMGAM, CtMGAM, and human pancreatic α-amylase (HPA) provide us an overall profile of the inhibitory ability of these inhibitors. Of all the inhibitors used in this paper, DNJ was the most effective inhibitor against MGAM; the K i values for the two catalytic domains were 1.41 and 2.04μM for NtMGAM and CtMGAM, respectively. Acarviostatins 2-03 and 3-03 were the best inhibitors against HPA with relatively high inhibitory activity against CtMGAM. The acarviostatins 2-03 and 3-03 inhibition constants, K i, for HPA were 15 and 14.3nM, and those for CtMGAM were 6.02 and 6.08μM, respectively. These results suggest that NtMGAM and CtMGAM differ in their substrate specificities and inhibitor tolerance despite their structural relationship. [Copyright &y& Elsevier]

Abstract: Cyclization by double reductive amination of d-xylo-hexos-5-ulose with methyl 6-aminohexanoate gave (methoxycarbonyl)pentyl-1-deoxynojirimycin. Reaction of the terminal carboxylic acid with N-dansyl-1,6-diaminohexane provided the corresponding chain-extended fluorescent derivative. By reaction with bis(6-dansylaminohexyl)amine, the corresponding branched di-N-dansyl compound was obtained. Both compounds are strong inhibitors of d-glucosidases and could also be shown to distinctly improve, at sub-inhibitory concentrations, the activity of β-glucocerebrosidase in a Gaucher fibroblast (N370S) cell-line through chaperoning of the enzyme to the lysosome. [Copyright &y& Elsevier]

Abstract: CuI-catalysed azide alkyne 1,3-dipolar cycloaddition (CuAAC) ‘click chemistry’ was used to assemble a library of 21 α-d- and β-d-glucopyranosyl triazoles, which were assessed as potential glycosidase inhibitors. In the course of this work, different reactivities of isomeric α- and β-glucopyranosyl azides under CuAAC conditions were noted. This difference was further investigated using competition reactions and rationalised on the basis of X-ray crystallographic data, which revealed significant differences in bond lengths within the azido groups of the α- and β-anomers. Structural studies also revealed a preference for perpendicular orientation of the sugar and triazole rings in both the α- and β-glucosyl triazoles in the solid state. The triazole library was assayed for inhibition of sweet almond β-glucosidase (GH1) and yeast α-glucosidase (GH13), which led to the identification of a set of glucosidase inhibitors effective in the 100μM range. The preference for inhibition of one enzyme over the other proved to be dependent on the anomeric configuration of the inhibitor, as expected. [Copyright &y& Elsevier]

Abstract: Glycosidases are very important enzymes involved in a variety of biochemical processes with a special importance to biotechnology, food industry, and pharmacology. Novel structurally simple inhibitors derived from cyclohexane-1,2-dicarboxylic acids were synthesized and tested against several fungal glycosidases from Aspergillus oryzae and Penicillium canescens. The presence of at least two carboxylic groups and one hydroxy group was essential for efficient inhibition. Significant selective inhibition was observed for α- and β-glucosidases, the magnitude of which depended on the configuration of substituents; inhibition increased for β-glucosidase by lengthening the alkoxy group of the inhibitor. [Copyright &y& Elsevier]

Abstract: Syzygium cumini seed kernel extracts were evaluated for the inhibition of α-glucosidase from mammalian (rat intestine), bacterial (Bacillus stearothermophilus), and yeast (Saccharomyces cerevisiae, baker’s yeast). In vitro studies using the mammalian α-glucosidase from rat intestine showed the extracts to be more effective in inhibiting maltase when compared to the acarbose control. Since acarbose is inactive against both the bacterial and the yeast enzymes, the extracts were compared to 1-deoxynojirimycin. We found all extracts to be more potent against α-glucosidase derived from B. stearothermophilus than that against the enzymes from either baker’s yeast or rat intestine. In an in vivo study using Goto–Kakizaki (GK) rats, the acetone extract was found to be a potent inhibitor of α-glucosidase hydrolysis of maltose when compared to untreated control animals. Therefore, these results point to the inhibition of α-glucosidase as a possible mechanism by which this herb acts as an anti-diabetic agent. [Copyright &y& Elsevier]

Abstract: The syntheses of nine S-alkylated, cyclic sulfonium-ions with varying alkyl chain lengths, as mimics of N-alkylated imino sugars, and their glucosidase inhibitory activities are described. The target compounds were synthesized by alkylation of 2,3,5-tri-O-benzyl-1,4-anhydro-4-thio-d-arabinitol at the ring sulfur atom using various alkyl halides, followed by deprotection using boron trichloride. Enzyme inhibitory assays against recombinant human maltase glucoamylase (MGA), a critical enzyme in the small intestine involved in the breakdown of glucose oligosaccharides into glucose itself, shows that they are effective inhibitors of MGA with K i values ranging from 6 to 75μM. [Copyright &y& Elsevier]

The inhibition kinetics for isoacarbose (a pseudotetrasaccharide, IsoAca) and acarviosine–glucose (pseudotrisaccharide, AcvGlc), both of which are derivatives of acarbose, were investigated with various types of α-glucosidases obtained from microorganisms, plants, and insects. IsoAca and AcvGlc, competitive inhibitors, allowed classification of α-glucosidases into two groups. Enzymes of the first group were strongly inhibited by AcvGlc and weakly by IsoAca, in which the Ki values of AcvGlc (0.35–3.0 μM) were 21- to 440-fold smaller than those of IsoAca. However, the second group of enzymes showed similar Ki values, ranging from 1.6 to 8.0 μM for both compounds. This classification for α-glucosidases is in total agreement with that based on the similarity of their amino acid sequences (family I and family II). This indicated that the α-glucosidase families I and II could be clearly distinguished based on their inhibition kinetic data for IsoAca and AcvGlc. The two groups of α-glucosidases seemed to recognize distinctively the extra reducing-terminal glucose unit in IsoAca. [Copyright &y& Elsevier]

Two sulfonium salts of 1,4-anhydro-4-thio-d-galactitol, with structures related to the known sulfonium salt glycosidase inhibitor, salacinol, have been synthesized as potential inhibitors of UDP-galactopyranose mutase. The synthetic strategy relies on the alkylation reaction of 1,4-anhydro-2,3,5,6-tetra-O-benzyl-4-thio-d-galactitol at the sulfur atom with 2,4-O-benzylidene-d- or -l-erythritol-1,3-cyclic sulfate. In each case, the reaction proceeded stereoselectively to yield only one stereoisomer at the stereogenic sulfur atom. The effect of the polar solvent, 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), in promoting high-yielding reactions is highlighted. The target compounds are then obtained by hydrogenolysis. [Copyright &y& Elsevier]