Synthesis of the enantiomers of XYLNAc and LYXNAc: comparison of β-N-acetylhexosaminidase inhibition by the 8 stereoisomers of 2-N-acetylamino-1,2,4-trideoxy-1,4-iminopentitols.

  title={Synthesis of the enantiomers of XYLNAc and LYXNAc: comparison of $\beta$-N-acetylhexosaminidase inhibition by the 8 stereoisomers of 2-N-acetylamino-1,2,4-trideoxy-1,4-iminopentitols.},
  author={E. Crabtree and R. Mart{\'i}nez and S. Nakagawa and I. Adachi and T. Butters and A. Kato and G. Fleet and A. F. G. Glawar},
  journal={Organic \& biomolecular chemistry},
  volume={12 23},
The enantiomers of XYLNAc (2-N-acetylamino-1,2,4-trideoxy-1,4-iminoxylitol) are prepared from the enantiomers of glucuronolactone; the synthesis of the enantiomers of LYXNAc (2-N-acetylamino-1,2,4-trideoxy-1,4-iminolyxitol) from an L-arabinono-δ-lactone and a D-ribono-δ-lactone is reported. A comparison is made of the inhibition of β-N-acetylhexosaminidases (HexNAcases) and α-N-acetylgalactosaminidase (α-GalNAcase) by 8 stereoisomeric 2-N-acetylamino-1,2,4-trideoxy-1,4-iminopentitols; their N… Expand
18 Citations
Stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc) and ureido-DNJNAc derivatives as new hexosaminidase inhibitors.
A stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc), the iminosugar analog of N-acetylglucosamine, with a high overall yield is described, being the first examples of neutral sp(2)-iminosugar-type inhibitors reported for these enzymes. Expand
Efficient stereoselective synthesis of 2-acetamido-1,2-dideoxyallonojirimycin (DAJNAc) and sp(2)-iminosugar conjugates: Novel hexosaminidase inhibitors with discrimination capabilities between the mature and precursor forms of the enzyme.
The ensemble of data suggests that the ratio between them, and not the inhibition potency towards the placenta enzyme, is a good indication of the chaperoning potential of TaySachs disease-associated mutant hexosaminidase. Expand
Thiazolylhydrazone dervatives as inhibitors for insect N-acetyl-β-d-hexosaminidase and chitinase
Abstract Insect chitinase and N-acetyl-β- d -hexosaminidases (Hex) are potential targets for developing new pesticides. Here, a series of thiazolylhydrazones I (with substituted group R1 at N3) andExpand
Asymmetric Synthesis of 3,4-Disubstituted 2-(Trifluoromethyl)pyrrolidines through Rearrangement of Chiral 2-(2,2,2-Trifluoro-1-hydroxyethyl)azetidines.
Reported pyrrolidines were N,O-debenzylated in a selective way and used for further synthetic elaboration to produce, for example, a CF3-substituted 2-oxa-4,7-diazabicyclo[3.3.0]octan-3-one system. Expand
Synthesis of Pyrrolidine Monocyclic Analogues of Pochonicine and Its Stereoisomers: Pursuit of Simplified Structures and Potent β-N-Acetylhexosaminidase Inhibition
The assay results reveal the importance of the N-acetylamino group and the possible right configurations of pyrrolidine ring required for this type of inhibitors. Expand
Design and synthesis of naphthalimide group-bearing thioglycosides as novel β-N-acetylhexosaminidases inhibitors
The determined structure–activity relationship as well as the established binding models provide the direction for further structure optimizations and the development of specific β-N-acetylhexosaminidase inhibitors. Expand
Structural essentials for β-N-acetylhexosaminidase inhibition by amides of prolines, pipecolic and azetidine carboxylic acids.
This paper explores the computer modelling aided design and synthesis of β-N-acetylhexosaminidase inhibitors along with their applicability to human disease treatment through biological evaluation inExpand
3-Azidoazetidines as the first scaffolds for β-amino azetidine carboxylic acid peptidomimetics: azetidine iminosugars containing an acetamido group do not inhibit β-N-acetylhexosaminidases
Abstract Stable amides and oligopeptides derived from methyl trans,trans -3-azido-4-hydroxymethyl- l -azetidine carboxylate, prepared in 19% yield from diacetone allose, is the first example of aExpand
Exploring NAG‐thiazoline and its derivatives as inhibitors of chitinolytic β‐acetylglucosaminidases
A bulky substituent was designed and synthesized on the thiazoline ring of NGT and the resulting compound was determined to be a submicromolar inhibitor of OfHex1 with a K i value of 0.13 μM, which is 600‐fold lower than NGT. Expand
Revisiting glycoside hydrolase family 20 β-N-acetyl-d-hexosaminidases: Crystal structures, physiological substrates and specific inhibitors.
A critical review summarizes recent research advances in GH20s, with a focus on their structural basis of substrate specificity as well as on inhibitor design. Expand


Efficient synthesis from d-lyxonolactone of 2-acetamido-1,4-imino-1,2,4-trideoxy-l-arabinitol LABNAc, a potent pyrrolidine inhibitor of hexosaminidases
The synthesis from d-lyxonolactone of 2-acetamido-1,4-imino-1,2,4-trideoxy-l-arabinitol LABNAc proceeded in an overall yield of 25%; the enantiomer, 2-acetamido-1,4-imino-1,2,4-trideoxy-d-arabinitolExpand
Potential glycosidase inhibitors: Synthesis of 1,4-dideoxy-1,4-imino derivatives of D-glucitol, D- and L-xylitol, D- and L-allitol, D- and L-talitol, and D-gulitol
Conversion of 2,3,5,6-tetra-O-benzyl-D-galactofuranose (19) into its oxime and subsequent treatment with methanesulphonyl chloride gave 2,3,5,6-tetra-O-benzyl-4-O-methylsulphonyl-D-galactonitrileExpand
Potent competitive inhibition of α-galactosidase and α-glucosidase activity by 1,4-dideoxy-1,4-iminopentitols: syntheses of 1,4-dideoxy-1,4-imino-d-lyxitol and of both enantiomers of 1,4-dideoxy-1,4-iminoarabinitol
Abstract The syntheses of 1,4-dideoxy-1,4-imino-D-lyxitol (3), 1,4-dideoxy-1,4-imino- d -arabinitol (4) and 1,4-dideoxy-1,4-imino- l -arabinitol (5) are reported; (3) is a potent competitiveExpand
Scalable syntheses of both enantiomers of DNJNAc and DGJNAc from glucuronolactone: the effect of N-alkylation on hexosaminidase inhibition.
Correlation of the in vitro inhibition with the cellular data, by using a free oligosaccharide analysis of the lysosomal enzyme inhibition, revealed the following structure-property relationship: hydrophobic side-chains preferentially promoted the intracellular access of iminosugars to those inhibitors with more-hydrophilic side-chain characteristics. Expand
Synthesis of (2R,3S,4R)-3,4-dihydroxyproline from D-ribonolactone; an approach to the synthesis of polyfunctionalised D-amino acids from sugar lactones. X-Ray molecular structures of 2-azido-3,4-O-(R)-benzylidene-2-deoxy-D-ribono-1,5-lactone, 2-azido-2-deoxy-D-ribono-1,4-lactone, and (2R,3S,3R)-3,4-
A general approach to the synthesis of polyfunctionalised amino acids from sugar lactones, in which nucleophilic displacement by azide ion of O-trifluoromethanesulphonyl esters adjacent to theExpand
An approach to 8 stereoisomers of homonojirimycin from (D)-glucose via kinetic & thermodynamic azido-γ-lactones.
Two epimeric azido-heptitols allow biotechnological transformations via Izumoring techniques to 8 of the 16 possible homonojirimycin analogues, 5 of which were isolated pure because of the lack of stereoselectivity of the final reductive amination. Expand
Nitrogen-in-the-ring pyranoses and furanoses: structural basis of inhibition of mammalian glycosidases.
Investigation of the contribution of epimerization, deoxygenation, and conformation to the potency of inhibition and specificity of mammalian glycosidases suggests that it superimposes well on the various glycosyl cations. Expand
Polyhydroxylated pyrrolidines from sugar lactomes: Synthesis of 1,4-dideoxy-1,4-imino-d-glucitol from d-galactonolactone and syntheses of 1,4-dideoxy-1,4-imino-d-allitol, 1,4-dideoxy-1,4-imino-d-ribitol, and (2s,3r,4s)-3,4-dihydroxyproline from d-gulonolactone
Abstract The use of readily available sugar lactones in the synthesis of polyhydroxylated pyrrolidines is illustrated by the preparation of the glucosidase inhibitor 1,4-dideoxy-1, 4-imino-D-glucitolExpand
Intermediates for incorporation of tetrahydroxypipecolic acid analogues of α- and β-d-mannopyranose into combinatorial libraries: unexpected nanomolar-range hexosaminidase inhibitors. Synthesis of α- and β-homomannojirimycin
Abstract Homoazasugars have the distinction as a class of natural products in that most of them have been synthesised before they were isolated. Syntheses of α- 1 and β-homomannojirimycin 2 rely onExpand
Looking glass inhibitors: synthesis of a potent naringinase inhibitor l-DIM [1,4-dideoxy-1,4-imino-l-mannitol], the enantiomer of DIM [1,4-dideoxy-1,4-imino-d-mannitol] a potent α-d-mannosidase inhibitor
Abstract The synthesis of l -DIM [1,4-dideoxy-1,4-imino- l -mannitol] and of 1,4-imino- d - glycero - l - talo -heptitol from d - glycero - d - gulo -heptono-1,4-lactone depends on the use ofExpand