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Publications (95)
A new class of compounds inhibiting de-O-glycosylation of proteins has been identified. Highly substituted diaminocyclopentanes are impressively selective reversible non-transition state O-β-N-acetyl-d-glucosaminidase (O-GlcNAcase) inhibitors. The ease of preparative access and remarkable biological activities provide highly viable leads for the de...
The aim of this work is to investigate if vinyl-modified carbohydrate compounds are suitable monomers for thin film polymerization via chemical vapor deposition in a proof-of-concept study. Synthetic carbohydrate-based polymers are explored as biodegradable, biocompatible, and biorenewable materials. A thin film of synthetic polymers bearing sugar...
A short survey on selected β‐galactosidase inhibitors as potential pharmacological chaperones for GM1‐gangliosidosis and Morquio B associated mutants of human lysosomal β‐galactosidase is provided highlighting recent developments in this particular area of lysosomal storage disorders and orphan diseases. Neurodegenerative GM1‐gangliosidosis and bon...
A convenient synthetic method to obtain d-galactose-substituted acylsilanes and acylgermanes is described. These acyl group 14 compounds are easily accessible in good yields. Their structural properties were analyzed by a combination of NMR, single crystal X-ray crystallography, and UV/vis spectroscopy. A d-galactose-substituted tetraacylgermane re...
A set of cyclopentanoid α-galactosidase ligands was prepared from a partially protected ω-eno-aldose via a reliable (2 + 3)-cycloaddition protocol with slightly modified conditions. The obtained N-benzylisoxazolidine ring was selectively opened and the configuration of the hydroxymethylgroup was inverted. Consecutive deprotection provided an aminoc...
The scope of a series of N-alkylated iminosugar based inhibitors in the d-gluco as well as d-xylo configuration towards their interaction with human lysosomal β-glucocerebrosidase has been evaluated. A versatile synthetic toolbox has been developed for the synthesis of N-alkylated iminosugar scaffolds conjugated to a variety of terminal groups via...
Glycosidase inhibitors have shown great potential as pharmacological chaperones for lysosomal storage diseases. In light of this, a series of new cyclopentanoid β-galactosidase inhibitors were prepared and their inhibitory and pharmacological chaperoning activities determined and compared with those of lipophilic analogs of the potent β-d-galactosi...
Cellulose is functionalized with different monosaccharides by the azide–alkyne click chemistry approach. Either azide or alkyne moieties are attached to the cellulose backbone and allowed to react with sugar moieties bearing the opposite clickable groups. Between 16% and 100% of the reactive sites at the polymer can be functionalized with sugar mol...
In tumor cells of more than 20 different cancer types, the CXCR4-CXCL12-axis is involved in multiple key processes including proliferation, survival, migration, invasion, and metastasis. Since data on this axis in diffuse large B cell lymphoma (DLBCL) are inconsistent and limited, we comprehensively studied the CXCR4-CXCL12-axis in our DLBCL cohort...
Modified 1,5-dideoxy-1,5-imino-d-xylitol analogues with different substitution patterns involving position C-1 and/or the ring nitrogen were prepared, which were designed to serve as precursors for the preparation of iminoxylitol-based ligands and tools for the elucidation and modulation of human lysosomal β-glucocerebrosidase. Biological evaluatio...
From 1,2;3,4-di-O-isopropylidene-d-galactopyranose, a series of highly functionalized branched-chain cyclopentanes was easily available. The initial partially protected cyclopentane tetraol is a versatile central intermediate and was exploited as subject to various highly regio- and stereoselective structural alterations with a view to prepare sele...
First Synthesis of 5-Fluoro-Isofagomine.
Overview of research done in this field by the Glycogroup at TU Graz. Explanation of the accomplished synthesis of 5-Fluoro-Isofagomine and outlook towards future development.
1-(N-Phenyl)amino-1-deoxy-α-D-manno-hept-2-ulose (2) and two multivalent BSA-based structures 7 and 8, D-manno-configured C-glycosyl-type compounds derived from an Amadori rearrangement, were evaluated as ligands for mannoside-specific lectins of various sources. The determination of the concentration corresponding to 50% of inhibition (IC 50 ) is...
From 1,2;3,4-di-O-isopropylidene-d-galactopyranose, a preliminary series of highly functionalized amino(hydroxymethyl)cyclopentanes was easily available. These amine-containing basic carbasugars featuring the d-galacto configuration are potent inhibitors of the GH20 β-d-hexosaminidases probed and may bear potential as regulators of N-acetyl-d-hexos...
Lysosomal storage diseases are hereditary disorders caused by mutations on genes encoding for one of the more than fifty lysosomal enzymes involved in the highly ordered degradation cascades of glycans, glycoconjugates, and other complex biomolecules in the lysosome. Several of these metabolic disorders are associated with the absence or the lack o...
Supporting Information
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 Staudinger/aza Wittig/Strecker (SAWS) multicomponent reaction (MCR) sequence applied to azidodeoxy carbohydrate substrates leads smoothly in good yield and with excellent stereoselectivity to versatile C-glycosyl iminoalditol analogues which prove useful as building blocks en route to functionalized C-glycosyl iminoalditols able to inhibit huma...
A new Staudinger/aza Wittig/Strecker multicomponent reaction sequence to C-1-cyano iminoalditols has been developed. When applied to 5-azidodeoxy-d-xylose and -d-glucose as substrates the method leads smoothly in good yield and with excellent stereoselectivity to respectively, 1,5-dideoxy-1,5-imino-d-idurono nitrile and 2,6-didesoxy-2,6-imino-d-gly...
Yarrowia lipolytica short chain dehydrogenase/reductase (YlSDR) was expressed in Escherichia coli, purified and characterized in vitro. The substrate scope for YlSDR mediated oxidation was investigated with alcohols and unprotected carbohydrates spectrophotometrically, revealing a preference for secondary compared to primary alcohols. In reduction...
The Amadori rearrangement was investigated as a potential method for the conjugation of carbohydrate moieties to suitable amino components. Starting from selected aldoheptoses, which are readily available by means of the Kiliani-Fischer C-elongation reaction of the corresponding aldohexoses, glycoconjugates presenting D-gluco, D-manno and D-galacto...
N-linked glycans play key roles in protein folding, stability, and function. Biosynthetic modification of N-linked glycans, within the endoplasmic reticulum, features sequential trimming and readornment steps. One unusual enzyme, endo-α-mannosidase, cleaves mannoside linkages internally within an N-linked glycan chain, short circuiting the classica...
Forty years of discoveries and research on imino sugars, which are carbohydrate analogues having a basic nitrogen atom instead of oxygen in the sugar ring and, acting as potent glycosidase inhibitors, have made considerable impact on our contemporary understanding of glycosidases. Imino sugars have helped to elucidate the catalytic machinery of gly...
N-(Dansylamino)hexylaminocarbonylpentyl-1,5-dideoxy-1,5-imino-D-galactitol, a strong competitive inhibitor of β-galactosidase, enhances residual β-galactosidase activities in fibroblasts and serves as lead en route to diagnostic compounds for tracking the fate of mutant β-gal as well as aberrant GM1 gangliosides by live cell imaging.
Unlike replacement therapy by infusion of exogenous recombinant lysosomal enzymes, pharmacological chaperones aim at a gain of function of endogenous gene products. Deficits resulting from missense mutations may become treatable by small, competitive inhibitors binding to the catalytical site and thus correcting the erroneous conformation of mutant...
Two simple and reliably accessible intermediates, N-carboxypentyl- and N-aminohexyl-1-deoxy-D-galactonojirimycin were employed for the synthesis of a set of terminally N-dansyl substituted derivatives. Reaction of the terminal carboxylic acid of N-carboxypentyl-1-deoxy-D-galactonojirimycin with N-dansyl-1,6-diaminohexane provided the chain-extended...
A collection of new reversible glycosidase inhibitors of the iminoalditol type featuring N-substituents containing perfluorinated regions has been prepared for evaluation of physicochemical, biochemical and diagnostic properties. The vast variety of feasible oligofluoro moieties allows for modular approaches to customised structures according to th...
New fluorescently-labelled sp(2)-iminosugars based on the 5N,6S-[N'-(4-aminobutyl)iminomethylidene]-6-thionojirimycin skeleton have been synthesized as photoprobes to monitor glycosidase binding. Dansyl, dapoxyl and coumarin fluorophores were appended to the terminal amino group at the N'-substituent by either sulfonamide or amide bridging reaction...
Biotin-iminosugar conjugates of different configuration such as D-gluco, D-galacto, L-ido as well as a furanoid representative in the D-manno configuration have been synthesised and exhibit powerful inhibition of beta-glucosidase from Agrobacterium sp. with K(i) values in the range of the respective parent compounds. Such molecular probes have pote...
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 br...
G(M1)-gangliosidosis (GM1) and Morquio B disease (MBD) are rare lysosomal storage disorders caused by mutations in the gene GLB1. Its main gene product, human acid beta-galactosidase (beta-Gal) degrades two functionally important molecules, G(M1)-ganglioside and keratan sulfate in brain and connective tissues, respectively. While GM1 is a severe, p...
N-Alkylation at the ring nitrogen of the D-galactosidase inhibitor 1-deoxygalactonojirimycin with a functionalised C ₆alkyl chain followed by modification with different aromatic substituents provided lipophilic 1-deoxygalactonojirimycin derivatives which exhibit inhibitory properties against β-glycosidases from E. coli and Agrobacterium sp. as wel...
Cyclisation by double reductive amination of 2-acetamino-2-deoxy-D-xylo-hexos-5-ulose with N-2 protected L-lysine derivatives provided 2-acetamino-1,2-dideoxynojirimycin derivatives without any observable epimer formation at C-5. Modifications on the lysine moiety gave access to lipophilic derivatives that exhibited improved hexosaminidase inhibito...
Background:
Since the first known use of antibiotics > 2,500 years ago, a research field with immense importance for the welfare of mankind has been developed. After a decrease in interest in this topic by the end of the 20th century the occurrence of (poly-)resistant strains of bacteria induced a revival of antibiotics research. Health systems ha...
Cyclization by double reductive amination of L-arabino-hexos-5-ulose with suitably protected D- as well as L-lysine derivatives provided 1-deoxygalactonojirimycin lysine hybrids without any observable epimer formation at C-5. Modifications on the lysine moiety by acylation gave access to lipophilic derivatives which exhibited excellent D-galactosid...
1,5-Dideoxy-1,5-iminoxylitolamino acid hybrids have been synthesized by cyclisation via a double reductive amination of xylo-pentodialdose and the respective amino groups of lysine as well as serine components. Further modification with aromatic substituents gave access to lipophilic derivatives. Kinetic studies revealed that all compounds exhibite...
The Amadori rearrangement was introduced as a key step for the conjugation of carbohydrate moieties with suitable amines such as aliphatic amines and amino acid derivatives. The rearrangement products were further transformed into the corresponding 1-N,2-O cyclic carbamates employing triphosgene to obtain anomerically stable glycoconjugates. The re...
1-Deoxymannojirimycin (8c) was synthesised from 2-amino-6-bromo-2,6-dideoxy-D-mannono-1,4-lactone (7) by intramolecular direct displacement of the C-6 bromine employing non-aqueous base treatment followed by reduction of the intermediate methyl ester. Likewise, using aqueous base at pH 12, ring closure took place by 5-exo attack on the 5,6-epoxide...
Three typical glycosidase-inhibiting iminoalditols were attached to a polyamine surface displayed on a silicon chip. Exposure to a representative beta-glucosidase revealed selective binding events reflecting the different structural features of the inhibitors probed in this study. This provides a proof-of-concept for the successful exploitation of...
Infectious diseases have remained a serious problem for society and concerned government organisations. Due to the dramatic increase of international transport of goods and passengers, dangerous microbial species and infectious diseases can be rapidly distributed over large distances. According to estimations by the World Health Organisation (WHO),...
Iminosugars, featuring a basic nitrogen at the hetero atom position in carbohydrate rings, gain increasing interest in the search for novel approaches towards cancer drug development. This compound class is known as competitive inhibitors of carbohydrate manipulation enzymes, such as glycosidases, which are involved in tumor cell invasion and migra...
Cyclization by double reductive amination of D-xylo-hexos-5-ulose with the terminal amino group of alpha-N-Boc-lysine methyl ester gave a 4:1-mixture of (1'R)-N-methoxycarbonyl-(1-N-Boc-amino)pentyl-1-deoxynojirimycin and the corresponding L-ido epimer whereas D-lyxo-hexos-5-ulose furnished the desired N-alkylated 1-deoxymannojirimycin derivative w...
Fünf passt auch: Die Kristallstruktur eines an Glycosidase gebundenen fünfgliedrigen Iminocyclitols wurde bestimmt (siehe Bild), und die Wechselwirkungen bei der Bindung dieses Inhibitors wurden mit denjenigen für die gängigen sechsgliedrigen Inhibitoren Isofagomin und Glucoimidazol und im Glycosyl-Enzym-Intermediat verglichen. Diese Daten können z...
For the past three decades, sugars and closely related mono- and bicyclic polyhydroxy compounds with heteroatoms other than oxygen in the ring, together with carbasugars in which the ring oxygen is replaced by a carbon atom, have accounted for a predominant portion of the carbohydrate literature not related to glycoside synthesis. This has occurred...
N -Acetyl-d-galactosamine (11), a very important naturally occurring building block of oligosaccharides, is easily accessible via the Heyns rearrangement of d-tagatose (3) with benzylamine. The short and efficient synthesis of various differently N -protected d-galactosamine derivatives is reported.
Based on our extensive studies of D-glucosidase inhibiting 2,5-dideoxy-2,5-imino-D-mannitol derivatives, we have been trying to create a series of fluorescent derivatives with a view to an 'inhibitory activity ruler' based on competitive displacement reactions of non-fluorescent inhibitors by fluorescent ones and vice versa, which can be performed...
1,5-Dideoxy-1,5-iminoalditols of various configurations as well as isofagomine were N-alkylated with non-polar straight chain spacer-arms by a set of simple standard procedures. The spacer-arms' terminal functional groups, primary amines, were employed to introduce fluorescent tags such as dansyl and dapoxyl moieties. Resulting derivatives in the D...
1,5-Dideoxy-1,5-imino-D-glucitol, the corresponding D-manno and L-ido epimers as well as the powerful beta-glucosidase inhibitor isofagomine were N-alkylated with di-, tri-, as well as tetraethylene glycol derived straight chain spacer arms by a set of simple standard procedures. The terminal functional groups of the spacer arms, primary amines, we...
Based on the reported glycosidase inhibitory activities of 1,6-dideoxy-1,6-imino-L-iditol, the corresponding aryl glycosides 4-nitrophenyl alpha- and beta-L -idoseptano side 7 and 8 were synthesised as possible glycosidase substrates. Despite their inherently larger size, these septanosides were indeed shown to be glycosidase substrates, albeit wea...
Based on glycosidase inhibitory activities of some known 1,4-iminoalditols, four aldofuranosides, (4-nitro)phenyl β-d-glucofuranoside, -β-d-galactofuranoside, -α-l-idofuranoside and -α-l-altrofuranoside, were identified as possible substrates of glucosidases and galactosidases. Three of them were found to be accepted by the β-glucosidase from Agrob...
A new approach for the discovery and subsequent structural elucidation of oligosaccharide-based inhibitors of α-amylases based
upon autoglucosylation of known α-glucosidase inhibitors is presented. This concept, highly analogous to what is hypothesized
to occur with acarbose, is demonstrated with the known α-glucosidase inhibitor, d-gluconohydroxim...
A range of new C-1 modified derivatives of the powerful glucosidase inhibitor 2,5-dideoxy-2,5-imino-D-mannitol has been synthesised and their biological activities probed with the beta-glucosidase from Agrobacterium sp. Ki values are compared with those of previously prepared close relatives. Findings suggest dramatic effects exerted by the aglycon...
Infectious diseases such as tuberculosis, malaria, the "simple flu" or HIV and HBV, are killing more than 50,000 people a day according to estimations by the World Health Organisation (WHO). Consequently, the development of biologically active agents in general, such as antibiotics and chemotherapeutics, is of great importance. Hand in hand with th...
Infectious diseases Such as tuberculosis, malaria, the "simple flu" or HIV and HBV, are killing more than 50,000 people a day according to estimations by the World Health Organisation (WHO). Consequently, the development of biologically active agents in general, such as antibiotics and chemotherapeutics, is of great importance. Hand in hand with th...
This appendix contains sections titled: Indolizidines Castanospermine and Analogs Lentiginosines, Swainsonines and Analogs
This appendix contains sections titled: Four-Membered Ring Five-Membered Rings, C4 Five-Membered Rings, C5 Five-Membered Rings, C6 1,4-Iminoalditols and Relatives 2,5-Iminoalditols and Relatives Five-Membered Rings, C7
This appendix contains sections titled: Six-Membered Rings, C6 allo-, altro-Configurations D-galacto-Configuration L-fuco-, L-galacto-Configurations GlucNAc-Mimics 1-Deoxynojirimycin and Analogs N-Modified
This appendix contains sections titled: Six-Membered Rings, C5 arabino-, ribo-, xylo-Configurations Azafagomines Pyrimidines
This appendix contains section titled: Calystegines
This appendix contains section titled: Pyrrolizidines
This appendix contains sections titled: Nagstatins and Other C-l/N-5 Containing Heterocycles Heterocycles Containing One Nitrogen Atom, NI Heterocycles Containing Two Nitrogen Atoms, N2 Heterocycles Containing Three Nitrogen Atoms, N3 Heterocycles Containing Four Nitrogen Atoms, N4
This appendix contains sections titled: 1-Deoxymannojirimycin and Analogs N-Modified O-Glycosylated or Ether Other Modifications talo-, rhamno-, D-gulo-Configurations Isofagomine and Analogs Siastatins and Analogs
This appendix contains sections titled: O-Glycosylated N-Modified and O-Glycosylated Other Modifications L-gluco-, L-gulo-, L-ido-Configurations
This appendix contains sections titled: Introduction Legend Contents Introduction Legend Contents
This appendix contains sections titled: Six-Membered Rings, C7 1,5-Iminoalditols 2,6-Iminoalditols Six-Membered Rings, C8 and Higher
This appendix contains section titled: Seven-Membered Rings
This appendix contains section titled: Quinolizidines
Iminosugars have emerged in the literature during mid-1960's as synthetic compounds. Around the same time, the first examples were found in Nature and their interesting enzyme inhibitory properties were recognised. Due to their powerful interference with glycohydrolases (glycosidases) as well as glycosyltransferases, quite a few representatives exh...
Displacement of the ring oxygen in a sugar by other heteroatoms such as nitrogen, phosphorus, or sulfur leads to pronounced changes of the physicochemical properties and, thus, the “information content” of the modified carbohydrate towards biochemical systems. Consequently, the altered biological properties of such a derivative with sugar modifying...
2-N-Acetyl-4-O-(β-D-galactopyranosyl)-D-glucosamine (N-acetyl-D-lactosamine), a very important building block of biologically relevant oligosaccharides such as sialyl Lewisx, is easily accessible via the Heyns rearrangement of the corresponding O-glycosylated ketohexose, D-lactulose. This approach can also be extended to other glucosamine derivativ...
Crystalline 1,3,4,5-tetra-O-acetyl-6-bromo-6-deoxy-keto-D-fructose was prepared by reaction of 1,3,4,5-tetra-O-acetyl-D-fructopyranose with triphenylphosphane dibromide in dichloromethane. Subsequent deprotection followed by reaction of the free 6-bromodeoxyfructofuranose with sodium azide in N,N-dimethylformamide furnished the corresponding 6-azid...
A range of partially protected ketoses was O-galactosylated with β-galactosidase from Aspergillus oryzae employing (4-nitro)phenyl β-D-alactopyranoside as the donor. This enzyme also accepted free D-tagatose as a substrate.
Amino-1,2,5-trideoxy-2,5-imino-D-mannitol was fluorescently tagged by reaction with dansyl chloride at N-1 or by attachment of a dansyl amide bearing spacer to this centre. Compounds obtained are highly potent inhibitors of beta-glucosidase exhibiting Ki values in the single figure nanomolar range. The 1-N-dansyl substituted inhibitor was successfu...
Novel derivatives of the D-glucosidase inhibitor 2,5-dideoxy-2,5-imino-D-mannitol bearing lipophilic aliphatic or aromatic amides attached to C-1 have been found to inhibit beta-glucosidase from Agrobacterium sp. in the nanomolar range. One of them, a coumarin derivative, ranks amongst the most active compounds in the class of reversible glycosidas...
1-Amino-1,2,5-trideoxy-2,5-imino-d-mannitol was fluorescently tagged by reaction with dansyl chloride at N-1 or by attachment of a dansyl amide bearing spacer to this centre. Compounds obtained are highly potent inhibitors of β-glucosidase exhibiting Ki values in the single figure nanomolar range. The 1-N-dansyl substituted inhibitor was successful...
The Amadori and Heyns rearrangements have been known to carbohydrate chemists for decades. Following an outline of their historical
development, a survey of the biological aspects, applications and alternative approaches will be given. Due to their nature,
both reactions suffer from a variety of preparative shortcomings; nonetheless, they are very...
By an Amadori rearrangement of easily available 5-azido-5-deoxy-D-glucofuranose with dibenzylamine and subsequent catalytic hydrogenation of the resulting 5-azido-1-(N,N-dibenzyl)amino-1,5-dideoxy-D-fructopyranose, 1-amino-1,2,5-trideoxy-2,5-imino-D-mannitol was obtained in only two steps and in excellent overall yield. Likewise, other amines were...
Disaccharides containing D-glucosamine at the reducing end can be conveniently synthesized in good yields from O-glycosylated D-fructoses by the title reaction [Eq. (a)]. With all the disaccharides investigated, the method proceeded—presumably because of the pronounced destabilizing interactions of the glycosyl residue at O-4 with the other polar g...
Disaccharide mit D-Glucosamin am reduzierenden Ende lassen sich elegant und in guten Ausbeuten durch die Titelreaktion aus O-glycosylierten D-Fructosen herstellen [Gl. (a)]. Die Methode verlief mit allen untersuchten Disacchariden – vermutlich wegen der ausgeprägten destabilisierenden Wechselwirkungen der Glycosylreste an O-4 mit den übrigen polare...
Propylene sulfite (PS) has been studied as a film-forming electrolyte additive for use in lithium ion battery electrolytes. Even small amounts in the order of 5 vol.% PS suppress propylene carbonate (PC) co-intercalation into graphite. In addition, a 1 M LiClO4/PC/PS (95:5 by volume) electrolyte is characterised by a high oxidation stability at a L...