Potential Glycosidase Inhibitors Research Articles

A concise synthesis of (−)-lentiginosine via an anti,syn-oxazine

A concise and stereocontrolled total synthesis of (−)-lentiginosine, a potent glycosidase inhibitor, has been achieved. Starting from anti,syn-oxazine as a chiral building block, the key features in these strategies are the Wittig reaction and cyclization.

Synthesis of l-3-epi-isofagomine, its homo-, n-butyl and bicyclic analogues from d-glucose as glycosidase inhibitors

Synthesis of l-3-epi-isofagomine, its homo-, n-butyl derivatives and its bicyclic analogue as potent glycosidase inhibitor has been achieved from readily available d-glucose. Inhibition of some commercially available glycosidases was also carried out with the newly synthesized inhibitors which showed reasonably good inhibitions (9.4–198.2μM). One of them (compound 11) showed selective inhibition of β-galactosidase.

ChemInform Abstract: Functionalization of Glycals Leading to 2‐Deoxy‐O‐glycosides, Aminosugars, Nitrosugars and Glycosidase Inhibitors: Our Experience

AbstractReview: 79 refs.

Functionalization of Glycals Leading to 2-Deoxy-O-glycosides, Aminosugars, Nitrosugars and Glycosidase Inhibitors: Our Experience

Glycals have been transformed into a variety of functionalized substrates which have been found to be useful in synthesizing some aminosugars, N-glycopeptides, nitrosugars and some iminosugars which are potential glycosidase inhibitors. An account of work that has been done in our laboratory is briefly discussed here.

Combined Chemical, Biological and Theoretical DFT‐QTAIM Study of Potent Glycosidase Inhibitors Based on Quaternary Indolizinium Salts

AbstractSix novel enantiopure epimeric indolizidinediols have been easily prepared in high yields by an effective and well‐established regioselective THF ring‐opening reaction as a key step. Quarternization of these species was also studied and comparison was made to the quaternizations of other substituted indolizidines. Importantly, a combined theoretical DFT‐QTAIM study has cast light on the various factors that explain the observed conformational selectivity. The inhibitory properties of the six synthesized indolizidines were then investigated against the recombinant Golgi α‐mannosidase‐IIb (dGMIIb) and lysosomal α‐mannosidase (dLM408), human homologues of Drosophila melanogaster. Among the tested compounds, two of them, 4a and 4b, exhibited a pH‐dependent inhibition of dGMIIb at the milimolar level (IC50 = 3.5 or 1.7 mM at pH 5.8 or 6.5, respectively) without affecting the activity of dLM408.

ChemInform Abstract: Targeted Drugs by Olefin Metathesis: Piperidine‐Based Iminosugars.

AbstractReview: [ca. 100 refs.]

Synthesis of conformationally-constrained thio(seleno)hydantoins and α-triazolyl lactones from d-arabinose as potential glycosidase inhibitors

We have explored the rich structural diversity provided by an α-azido ester derived from d-arabinose as the source of sugar templates with reduced conformational flexibility. Using transient α-thioureido(selenoureido) esters we have prepared spiranic thio(seleno)hydantoins at the C-3 position of the sugar moiety. In this context, the first example of a stable spiranic α-lactam (or aziridinone) was isolated as a by-product in the hydrogenolysis of the starting α-azido ester. Furthermore, using copper(I)-catalyzed azido–alkyne cycloaddition (click chemistry), we have accessed bicyclic cis-fused α-triazolyl lactones fixed in the furanose form. Spiranic thiohydantoins turned out to be moderate, though selective, inhibitors of glycosidases, whereas their selenium isosters behaved as good free radical scavengers.

L-Isofucoselenofagomine and derivatives: dual activities as antioxidants and as glycosidase inhibitors

The synthesis of a series of l-fuco-configured selenosugars, isosters of the potent glycosidase inhibitor isofucofagomine has been accomplished by a double nucleophilic displacement of a dimesylated derivative with selenide anion generated in situ. Se-Alkylation and oxidation of the corresponding selenane afforded a selenonium and a selenoxide, respectively. The biological activities of such compounds have been evaluated, finding a dual activity caused by the presence of the selenium atom: the selenane exerted a good glutathione peroxidase mimicry by efficiently scavenging H2O2 in the presence of thiols, whereas the stable selenoxide derivative was found to be the first example of a selenosugar acting as a good α-l-fucosidase inhibitor.

Targeted drugs by olefin metathesis: piperidine-based iminosugars

Examining advances in the class of natural and non-natural piperidine azasugars, important therapeutic agents and potent glycosidase inhibitors, this review looks at syntheses applying olefin metathesis as a highly efficient key step and gateway strategy for discovery of better iminosugar leads for treatment of widespread affections like viral and metabolic diseases. Amply illustrated is how ring-closing metathesis (RCM and RCEYM), promoted by commercial ruthenium alkylidene catalysts, manage to construct the common tetrahydropyridine core while cross-metathesis (CM), starting from this generic scaffold, provides general access to families of novel azasugars. Special consideration is given to high-profile iminosugar drugs of this class (1-deoxynojirimycin and congeners, adenophorine, fagomine, isofagomine and some of their N- and C-substituted analogues) stressing upon newest trends for enhancing biological activity and modulating previously unexploited targets in multispecific therapies.

Diversity-oriented syntheses of 7-substituted lentiginosines

Diversity-oriented synthesis of derivatives of the potent glycosidase inhibitor lentiginosine can be achieved in an efficient and versatile way by two modular approaches on key intermediates. After assembling the indolizidine ring system through 1,3-dipolar cycloaddition of a dihydroxylated pyrroline N-oxide with 4-butenol followed by elaboration of the isoxazolidine moiety, the 7-amino and 7-azido derivatives synthesized can be conjugated with functionalised chains by coupling, respectively, with an amino acid, or an alkyne in copper-catalyzed Huisgen cycloadditions.

Synthesis of polyhydroxy 7- and N-alkyl-azepanes as potent glycosidase inhibitors

An effective synthetic method for polyhydroxylated azepanes that contain an alkyl group (Me or Bu) at either the 7- or N-positions is developed. The synthetic routes are accomplished in eight to ten steps from d-(−)-quinic acid. Among the compounds synthesized, the polyhydroxy 7-butyl azepane (compound 3), which possessed the R-configuration at C-7 position, is shown to give potent inhibition against β-galactosidase (IC 50 = 3 μM). Preliminary biological data indicate that the length of alkyl groups along with the proper stereochemistry at the C-7 position is essential for acquiring extra binding affinity. Using similar synthetic routes, the polyhydroxy N-methyl and N-butyl azepanes are synthesized for the comparison of their biological activities.

Asymmetric synthesis of hydroxy-skipped bishomo-inositols as potential glycosidase inhibitors

Four isomeric hydroxy-skipped bishomo-inositol analogs have been synthesized from both enantiomers of 5-hydroxymethyl-2-cyclohexenone. Sharpless asymmetric dihydroxylation and substrate-directed anionic hydroxymethylation are the key reactions which have been employed successfully for the synthesis of new cyclitols. The synthesized cyclitols have been screened for their inhibitory effect on α- and β-glycosidases.

ChemInform Abstract: A New Family of Five-Carbon Iminoalditols which are Potent Glycosidase Inhibitors.

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Medicinal Chemistry of Aminocyclitols

Aminocyclitols comprise an important group of compounds with remarkable biological activities. From a structural standpoint, aminocyclitols are amino polyhydroxy cycloalkanes that can be found in nature in several families of natural products. Among them, the aminoglycoside antibiotics, since the discovery of streptomycin, have become particularly relevant at the forefront of the antibacterial treatment. Another group of aminocyclitols, generally referred to as aminocarbasugars, have been found as key structural components of some families of alkaloids that have evolved as suitable leads for the development of potent glycosidase inhibitors with a vast array of applications in medicinal chemistry, both as therapeutically useful agents as well as valuable pharmacological tools. On the other hand, the aminocyclitol moiety has been used by medicinal chemists as a versatile scaffold in drug design. Thus, in the antiviral arena, it is found as the key component of several families of carbocyclic nucleoside analogues, designed as metabolically stable surrogates of the natural nucleosides. Finally, in a still relatively unexplored area, some aminocyclitol derivatives are being used as key components of artificial receptors for which promising applications in drug research can be envisaged. In all cases, the development of the modern regio- and stereoselective synthetic methodologies enables a large variety of stereochemically defined aminocyclitol analogues in order to study in depth the influence of this moiety on the structure-activity relationships from a given lead.

Synthesis of unnatural pentahydroxylated pyrrolizidines: 5-epi- and 5,7a-di-epi-hyacinthacine C1

Stereocontrolled synthesis of 5-epi- and 5,7a-di-epi-hyacinthacine C1 (7 and 8), two potential glycosidase inhibitors are described using α,β-unsaturated ketone 9 as homochiral starting material. The key step in the synthesis is the highly diastereoselective dihydroxylation reaction of 9, that allows the obtention of a single bis-hydroxylated ketone (10). Further derivatization into two epimeric mesylate esters followed by internal cyclization form the pyrrolizidinic compounds 7 and 8. This type of compounds can be useful in glycobiology due to their ability to inhibit carbohydrate-processing enzymes.

ChemInform Abstract: A Short Synthesis of Polyhydroxylated Piperidines by Aldol Reaction of Chelated Amino Acid Ester Enolates.

Aldol reactions of a chelated glycine ester enolate with a chiral aldehyde gives rise to the corresponding polyhydroxylated amino acid with excellent induced diastereoselectivity. These oxygenated amino acids can be converted into polyhydroxylated pipecolinic acids and azasugars by cyclization using the Mitsunobu reaction. An interesting epimerization was observed during the cyclization. The potential glycosidase inhibitor 1-deoxyaltronojirimycin (8b) was synthesized by this approach in a highly stereoselective fashion.

ChemInform Abstract: Synthesis of (+)-Casuarine.

The first synthesis of (+)-casuarine ((+)-6), a pentahydroxy pyrrolizidine alkaloid of the alexine/australine subclass, is described. The key step is a tandem [4 + 2]/[3 + 2] nitroalkene cycloaddition involving nitrobenzoate 13, chiral vinyl ether 16c, and vinyl silane 10, which establishes five of the six stereocenters present in this potent glycosidase inhibitor. The completion of the synthesis requires only four additional steps to deliver the final product in 20% overall yield.

Synthesis of α- and β- d-glucopyranosyl triazoles by CuAAC ‘click chemistry’: reactant tolerance, reaction rate, product structure and glucosidase inhibitory properties

Cu I-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 100 μM range. The preference for inhibition of one enzyme over the other proved to be dependent on the anomeric configuration of the inhibitor, as expected.

Simple, Selective, and Rapid Quantification of 1‐Deoxynojirimycin in Mulberry Leaf Products by High‐Performance Anion‐Exchange Chromatography with Pulsed Amperometric Detection

1-Deoxynojirimycin (DNJ) occurs in mulberry and other plants and is a highly potent glycosidase inhibitor reported to suppress blood glucose levels, thus preventing diabetes. Derivatization is required for quantification of DNJ upon use of spectral detection methods. Because of this difficulty, the DNJ contents of mulberry-based food products are rarely stated, even if DNJ is their active component. A simple, selective, and rapid method of high-performance anion-exchange chromatography with pulsed amperometric detection (HPAEC-PAD) to quantify DNJ in mulberry-based food products was developed. Stability testing of DNJ under heat treatment was also performed. A water extract of mulberry tea sample was subjected to HPAEC-PAD in a CarboPac MA1 column with a sodium hydroxide gradient. DNJ was clearly separated at a retention time of 7.26 min without interference and was selectively detected in the water extract. The detection limit was 5 ng. Heat stability studies suggested that DNJ was heat stable. HPAEC-PAD was not subject to interference, was highly selective for DNJ, and was superior to other high-performance liquid chromatography (HPLC) techniques in terms of sample preparation, resolution, and sensitivity. The method allowed simple, selective, and rapid analysis of DNJ in food matrices and might be useful for development of mulberry-based food products. Heat treatment could be an option for sterilizing mulberry-based products.

An Expeditious Synthesis of Iminosugars

A short and expedient synthesis of the potent glycosidase inhibitors, 1-deoxynojirimycin, miglitol, miglustat, 1-deoxymannojirimycin, and 1-deoxygalactonojirimycin is presented.