Potential Glycosidase Inhibitors Research Articles

Synthesis of thioswainsonine as a potential glycosidase inhibitor

The synthesis of a bicyclic sulfonium-ion analogue of a naturally occurring glycosidase inhibitor, swainsonine, in which the bridgehead nitrogen atom is replaced by a sulfonium ion, has been achieved by a multi-step synthesis starting from 1,4-anhydro-2,3-di- O-benzyl-4-thio- d-lyxitol. The synthetic strategy relies on the intramolecular displacement of a leaving group on a pendant acyclic chain by a cyclic thioether. This bicyclic sulfonium salt will serve as a candidate to test the hypothesis that a sulfonium salt carrying a permanent positive charge would be an effective glycosidase inhibitor.

Synthesis of Novel Bicyclic Ketals of Galacturonic Acid as Potential Glycosidase Inhibitors

A synthesis of novel bicyclic ketals of galacturonic acid is described. The key cyclisation step was realised under acidic anhydrous conditions in very good yield. X-ray crystal structure analysis determined the correct regio- and stereochemistry.

Synthesis of zwitterionic selenonium and sulfonium sulfates from D-mannose as potential glycosidase inhibitors

Four chain-extended analogues of the naturally occurring glycosidase inhibitor salacinol were synthesized for structure–activity studies with different glycosidase enzymes. The syntheses involved the reaction of isopropylidene-protected 1,4-thio- and 1,4-seleno-D-talitols and 1,5-thio- and 1,5-seleno-L-gulitols, derived from D-mannose, with a benzylidene- and isopropylidene-protected 1,3-cyclic sulfate, also derived from D-mannose. Deprotection of the products afforded the novel selenonium and sulfonium sulfates composed of heterocyclic five- and six-membered ring core structures with pendant polyhydroxylated, acyclic chains of six carbon atoms.Key words: glycosidase inhibitors, zwitterionic selenonium and sulfonium sulfates, cyclic sulfate

Novel five-membered iminocyclitol derivatives as selective and potent glycosidase inhibitors: new structures for antivirals and osteoarthritis.

A novel 5‐membered iminocyclitol derivative was found to be a potent and selective inhibitor of the glycoprotein‐processing α‐glucosidase with a K i value of 53 nm. This compound was further derivatized to antiviral agents against Japanese encephalitis virus, dengue virus serotype 2 (DEN‐2), human SARS coronavirus, and human β‐hexosaminidase (K i =2.6 nm), a new target for the development of osteoarthritis therapeutics.

Synthesis, glycosidase activity and X-ray crystallography of 3-amino-sugars

The cleavage of two sugar epoxides, methyl 2,3-anhydro-alpha-D-mannopyranoside and 2,3-anhydro-alpha-D-allopyranoside, with amines is presented as a method for preparing a library of 3-amino-sugars (methyl 3-amino-3-deoxy-alpha-D-altropyranosides and methyl 3-amino-3-deoxy-alpha-D-glucopyranosides) as potential glycosidase inhibitors. Several of the altropyranosides were micromolar inhibitors of bovine liver beta-galactosidase and almond beta-glucosidase. X-ray crystal structures were determined for one of the methyl 3-amino-3-deoxy-alpha-D-altropyranosides, 4t, and one of the methyl 3-amino-3-deoxy-alpha-D-glucopyranosides, 6d.

C-Glycosides and Aza-C-Glycosides as Potential Glycosidase and Glycosyltransferase Inhibitors

Glycosylation as one of most important post-translational modification of gene products is often critical to specific cellular biological functions. Since elevated glycoprocessing enzyme activities have been implicated in the development of various diseases including cancer metastasis, glycosidases and glycosyltransferases are considered as therapeutic targets. Azasugars, the first generation of enzyme inhibitors, have been extensively investigated and two azasugar-based drugs (Miglitol and Miglustat) have been approved. Aza-C-glycosides, molecules with an azasugar core and various C-aglycons attached at the pseudo anomeric center, have the potential to become the second-generation inhibitors with improved specificity and membrane permeability. In this review, C-glycosides, aza-C-glycosides, and aza-C-disaccharides are introduced as glycoprocessing enzyme inhibitors. The synthetic approaches toward those molecules are described based on the key reactions, which include reductive amination, nucleophilic ring opening of epoxides, nucleophilic addition to imines (C=N), and hetero-Michael additions. Aza-C-glycoside-based libraries are also described for the discovery of promising second-generation inhibitors.

Recent Advances in the Total Synthesis of Piperidine Azasugars

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis and Comparative Glycosidase Inhibitory Properties of Reducing Castanospermine Analogues

AbstractThe 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 α‐glycosides. These analogs of the natural alkaloid showed a higher selectivity in the inhibition of α‐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 α‐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)

Recent Advances in the Total Synthesis of Piperidine Azasugars

AbstractSince the discovery of nojirimycin, a glycosidase inhibitor, polyhydroxylated piperidines (also called azasugars: the ring O‐atom of a carbohydrate is replaced by nitrogen) have attracted considerable attention and have been the target of numerous synthetic strategies during the last decade. The efficient synthesis of naturally occurring azasugars and their analogs is of considerable importance due to their potential glycosidase inhibitor properties. Some of them have been widely investigated as candidates for drugs to treat a variety of carbohydrate‐mediated diseases such as diabetes, viral infections, including HIV, cancer metastasis, hepatitis, and Gaucher’s disease. This microreview focuses on recent syntheses of azasugars. In addition, the biology of these compounds is briefly considered. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2005)

Stereoselective Synthesis of Polyhydroxylated Indolizidines Based on Pyridinium Salt Photochemistry and Ring Rearrangement Metathesis.

AbstractFor Abstract see ChemInform Abstract in Full Text.

The Intramolecular Conjugate Addition of Benzylamine to a D‐Glucose Derived α,β‐Unsaturated Ester: An Efficient Synthesis of Trihydroxylated Pyrrolidine Alkaloids as Potential Glycosidase Inhibitors.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Electrophilic Bromination of N‐Acylated Cyclohex‐3‐en‐1‐amines: Synthesis of 7‐Azanorbornanes

AbstractThe intramolecular bromo‐amidation and the dibromination‐cyclisation of the N‐acylcyclohex‐3‐en‐1‐amines 4, 8, 9, 11, 13, 14, and 16 was studied in view of the synthesis of bicyclic amines that are of interest as building blocks and potential glycosidase inhibitors. The trifluoroacetamides 4, 9, and 14 reacted with N‐bromosuccinimide (NBS) in AcOH to give dihydro‐1,3‐oxazines in good yields. The stereoselectivity of the dibromination of the alkenes 8 and 9 depends on the nature of the protecting group, the reagent, and the reaction conditions. Br2 in CH2Cl2 transformed the alkenes 8 and 9 predominantly into diaxial trans,trans‐dibromides. Bromination of 9 with PhMe3NBr3 or with Br2 in the presence of Et4NBr gave predominantly the diequatorial trans,cis‐27 besides some trans,trans‐28. A similar bromination of the C(5)‐substituted N‐acyl‐4‐aminocyclohexenes 11, 13, 14, and 16 with PhMe3NBr3 was accompanied by intramolecular side reactions that were suppressed by the addition of excess Et4NBr. Under these conditions, 11 gave diastereoselectively trans‐dibromides, while its reaction with Br2 gave trans‐dibromides along with the dihydrooxazinone 31. Also the carbamate 13 reacted with PhMe3NBr3/Et4NBr selectively to the trans‐dibromide 32 and with Br2 to the trans‐dibromides 32 and 33, the dihydrooxazinone 34, and the bicyclic ether 35. Similarly, the trifluoroacetamide 14 provided the dibromide 36 (89%), while its reaction with Br2 led to the dihydrooxazine 22, and the dibromides 36 and 37. The N‐benzyl‐N‐Boc derivative 16 did not yield any dibromide; it reacted with PhMe3NBr3/Et4NBr to the dihydrooxazinone 38, and with Br2 to the oxazinone 38 and the bicyclic ether 39. The high stereoselectivity of the bromination with PhMe3NBr3/Et4NBr suggests an anchimeric assistance of the NHR substituent. Deprotection, cyclisation, and carbamoylation transformed the dibromides 27, 29, and 32 into the 7‐azanorbornanes 42, 49, and 53. The diols 45 and 57 were obtained from 42 and 53 via HBr elimination and stereoselective dihydroxylation; they proved weak inhibitors of several glycosidases. In no case could the formation of a bicyclic azetidine (6‐azabicyclo[3.1.1]heptane) from the dibromides 26 and 30 be observed.

The intramolecular conjugate addition of benzylamine to a d-glucose derived α,β-unsaturated ester: an efficient synthesis of trihydroxylated pyrrolidine alkaloids as potential glycosidase inhibitors

A short and efficient synthesis of 1,4,5-trideoxy-1,4-imino- l- xylo-hexitol 2a and 1,4,5-trideoxy-1,4-imino- d- arabino-hexitol 2b is reported using the intramolecular conjugate addition of in situ generated benzylamine to the α,β-unsaturated ester 4 , derived from d-glucose, as the key step.

The First Synthesis of Substituted Azepanes Mimicking Monosaccharides: A New Class of Potent Glycosidase Inhibitors.

AbstractFor Abstract see ChemInform Abstract in Full Text.

A Novel Approach to Both the Enantiomers of Potent Glycosidase Inhibitor Isofagomine via PET-Promoted Cyclization of 1-[Benzyl(trimethylsilyl-methyl)amino]-1,4,5-trideoxy-2,3-O-(1-methylethylidene)-threo-pent-4-ynitol

The cyclization of PET-generated α-trimethylsilylmethylamine radical cation to a tethered acetylene moiety has been exploited to solve the problem of the generation of an aminomethyl group next to a stereocenter in the synthesis of 1-N-iminosugar type glycosidase inhibitors. Its success is demonstrated by the synthesis of (+)- as well as (-)-isofagomine, an extremely potent β -glucosidase inhibitor of the 1-N-iminosugar class.

Stereoselective synthesis of polyhydroxylated indolizidines based on pyridinium salt photochemistry and ring rearrangement metathesis.

Ruthenium-catalyzed ring rearrangement metathesis (RRM) reactions of stereochemically diverse, differentially protected 4-N-allylacetamidocyclopenten-3,5-diols, prepared by using pyridinium salt photochemistry, have been explored as part of a program to develop novel routes for the synthesis of polyhydroxylated indolizidines. The RRM reactions, which produce selectively protected 1-acetyl-2-allyl-3-hydroxy-1,2,3,6-tetrahydropyridines, were found to take in high yields and with high levels of regioselectivity. The significance of RRM reactions of 4-N-allylacetamidocyclopenten-3,5-diols in the context of polyhydroxylated indolizidine synthesis is demonstrated by an application to the concise preparation of the potent glycosidase inhibitor, (-)-swainsonine.

Discovery of picomolar slow tight-binding inhibitors of alpha-fucosidase.

Glycosidase inhibitors have shown great medicinal and pharmaceutical values as exemplified by the therapeutic treatment of influenza virus and non-insulin-dependent diabetes. We herein report the discovery of picomolar slow tight-binding inhibitors 2-5 against the alpha-fucosidase from Corynebacterium sp. by a rapid screening for an optimal aglycon attached to 1-aminomethyl fuconojirimycin (1). The time-dependent inhibition displays the progressive tightening of enzyme-inhibitor complex from a low nanomolar K(i) to picomolar K(i)* value. Particularly compound 2 with a K(i)* of 0.46 pM represents the most potent glycosidase inhibitor to date. The effect of compound 3 on the intrinsic fluorescence of alpha-fucosidase is both time- and concentration-dependent in a saturation-type manner, which is consistent with the initial formation of a rapid equilibrium complex of enzyme and inhibitor (E.I), followed by the slower formation of a tightly bound enzyme-inhibitor complex (E.I*). The binding affinity increases 3.5 x 10(4)-fold from 1 (K(i) = 16.3 nM) to 2 (K(i)* = 0.46 pM). This work clearly demonstrates the effectiveness of our combinatorial approach leading to the rapid discovery of potent inhibitors.

In situ 1,3‐Dipolar Azide Cycloaddition Reaction: Synthesis of Functionalized D‐Glucose Based Chiral Piperidine and Oxazepine Analogues.

Abstract Functionalized furanose-fused piperidines 4-6 and oxazepines 15-17 , useful precursors for structurally unique bioactive nucleosides as well as for potential glycosidase inhibitors, have been synthesized by the application of 1,3-dipolar azide cycloaddition (DAC) reaction on d -glucose based substrates. The strategy works well even with the nucleoside analogue 8 , affording the bicyclic nucleoside analogues 11 and 12 .

Synthesis of Amino Carba Sugars and Conformationally Restricted Polyhydroxy γ‐Amino Acids from (−)‐Quinic Acid

AbstractEfficient syntheses of two novel positional stereoisomers of valiolamine, a potent glycosidase inhibitor, and two polyhydroxy γ‐amino acids are reported. The syntheses involve regio‐ and stereoselective azidolysis of epoxides by trimethylsilyl azide with BF3·OEt2 as Lewis acid. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)

Glycosylamidines as Potent Selective and Easily Accessible Glycosidase Inhibitors and Their Application to Affinity Chromatography

AbstractFor Abstract see ChemInform Abstract in Full Text.