Efficient synthesis from d-lyxonolactone of 2-acetamido-1,4-imino-1,2,4-trideoxy-l-arabinitol LABNAc, a potent pyrrolidine inhibitor of hexosaminidases

Rountree, J. S. Shane; Butters, Terry D.; Wormald, Mark R.; Dwek, Raymond A.; Asano, Naoki; Ikeda, Kyoko; Evinson, Emma L.; Nash, Robert J.; Fleet, George W. J.

doi:10.1016/j.tetlet.2007.04.041

Cited by 29 publications

(11 citation statements)

References 45 publications

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“…Phase 2 clinical trials of DGJ 12 have been completed recently, and positive results were announced. Therefore, iminosugars and derivatives were chosen as our desired target compounds for the inhibition of N ‐acetylhexosaminidases, specifically DABNAc 5 and LABNAc 1 , the syntheses and preliminary biological data for which were described in a recent communication 23…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Enantiomeric β‐N‐Acetylhexosaminidase Inhibitors LABNAc and DABNAc as Potential Agents against Tay‐Sachs and Sandhoff Disease

et al. 2009

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N-Acetylhexosaminidases are of considerable importance in mammals and are involved in various significant biological processes. In humans, deficiencies of these enzymes in the lysosome, resulting from inherited genetic defects, cause the glycolipid storage disorders Tay-Sachs and Sandhoff diseases. One promising therapy for these diseases involves the use of beta-N-acetylhexosaminidase inhibitors as chemical chaperones to enhance the enzyme activity above sub-critical levels. Herein we describe the synthesis and biological evaluation of a potent inhibitor, 2-acetamido-1,4-imino-1,2,4-trideoxy-L-arabinitol (LABNAc), in a high-yielding 11-step procedure from D-lyxonolactone. The N-benzyl and N-butyl analogues were also prepared and found to be potent inhibitors. The enantiomers DABNAc and NBn-DABNAc were synthesised from L-lyxonolactone, and were also evaluated. The L-iminosugar LABNAc and its derivatives were found to be potent noncompetitive inhibitors of some beta-N-acetylhexosaminidases, while the D-iminosugar DABNAc and its derivatives were found to be weaker competitive inhibitors. These results support previous work postulating that D-iminosugar mimics inhibit D-glycohydrolases competitively, and that their corresponding L-enantiomers show noncompetitive inhibition of these enzymes. Molecular modelling studies confirm that the spatial organisation in enantiomeric inhibitors leads to a different overlay with the monosaccharide substrate. Initial cell-based studies suggest that NBn-LABNAc can act as a chemical chaperone to enhance the deficient enzyme's activity to levels that may cause a positive pharmacological effect. LABNAc, NBn-LABNAc, and NBu-LABNAc are potent and selective inhibitors of beta-N-acetylhexosaminidase and may be useful as therapeutic agents for treating adult Tay-Sachs and Sandhoff diseases.

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Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Enantiomeric β‐N‐Acetylhexosaminidase Inhibitors LABNAc and DABNAc as Potential Agents against Tay‐Sachs and Sandhoff Disease

et al. 2009

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“…Media and PBS were from Invitrogen (Paisley, UK). β-Hexosaminidase inhibitor SR1 (2-acetamido-1,4-imino-1,2,4-trideoxy-L-arabinitol) was synthesised as described previously [14]. Ceramide glycanase from Hirudu medicinalis and ß-hexosaminidase and α-mannosidase from jack bean meal were purified in-house.…”

Section: Methodsmentioning

confidence: 99%

“…Results SR1 causes accumulation of N-acetylhexosamine terminating GSL and OS in RAW cells SR1 is a novel pyrrolidine imino sugar that stereochemically resembles N-acetylhexosamine [14]. In murine RAW264.7 macrophage-like cell extracts, this compound inhibited β-hexosaminidase activity at low micromolar concentrations (Table 1) in a predominantly noncompetitive manner using artificial substrates, as determined by Lineweaver-Burk plots (data not shown), consistent with the inhibition of other mammalian and plant-derived hexosaminidases [20].…”

Section: Methodsmentioning

confidence: 99%

Lysosomal storage of oligosaccharide and glycosphingolipid in imino sugar treated cells

et al. 2010

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Sandhoff and Tay-Sachs disease are autosomal recessive GM2 gangliosidoses where a deficiency of lysosomal beta-hexosaminidase results in storage of glycoconjugates. Imino sugar (2-acetamido-1,4-imino-1,2,4-trideoxy-L-arabinitol) inhibition of beta-hexosaminidase in murine RAW264.7 macrophage-like cells led to lysosomal storage of glycoconjugates that were characterised structurally using fluorescence labelling of the free or glycolipid-derived oligosaccharides followed by HPLC and mass spectrometry. Stored glycoconjugates were confirmed as containing non-reducing GlcNAc or GalNAc residues resulting from the incomplete degradation of N-linked glycoprotein oligosaccharide and glycolipids, respectively. When substrate reduction therapeutics N-butyl-deoxynojirimycin (NB-DNJ) or N-butyldeoxygalactonojirimycin (NB-DGJ) were applied to the storage phenotype cells, an increase in glucosylated and galactosylated oligosaccharide species was observed due to endoplasmic reticulum alpha-glucosidases and lysosomal beta-galactosidase inhibition, respectively. Hexosaminidase inhibition triggered a tightly regulated cytokine-mediated inflammatory response that was normalised using imino sugars NB-DNJ and NB-DGJ, which restored the GM2 ganglioside storage burden but failed to reduce the levels of GA2 glycolipid or glycoprotein-derived N-linked oligosaccharides. Using a chemically induced gangliosidosis phenotype that can be modulated with substrate lowering drugs, the critical role of GM2 ganglioside in the progression of inflammatory disease is also demonstrated.

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“…The N-acetylamino group is the common structural feature that distinguishes these natural products from the other iminosugars [14]. A diverse range of potent synthetic β-HexNAcase iminosugar inhibitors have been reported including pyrrolidines (4 [15][16][17], 5 [18,19], 6 [20,21] and 7 [22]), piperidines (8 [23,24], 9 [25] and 10 [26]), azepanes (11 [27-29]) and azetidines (12 [30] and 13 [31]); almost all of them contain an N-acetylamino group ( Figure 2) [32]. The novel structure and inhibition properties of pochonicine (1) led to the rapid report of total syntheses [2], together with its enantiomer [33] and analogues [34].…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Pyrrolidine Monocyclic Analogues of Pochonicine and Its Stereoisomers: Pursuit of Simplified Structures and Potent β-N-Acetylhexosaminidase Inhibition

et al. 2020

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Ten pairs of pyrrolidine analogues of pochonicine and its stereoisomers have been synthesized from four enantiomeric pairs of polyhydroxylated cyclic nitrones. Among the ten N-acetylamino pyrrolidine analogues, only compounds with 2,5-dideoxy-2,5-imino-d-mannitol (DMDP) and pochonicine (1) configurations showed potent inhibition of β-N-acetylhexosaminidases (β-HexNAcases); while 1-amino analogues lost almost all their inhibitions towards the tested enzymes. 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.

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Efficient synthesis from d-lyxonolactone of 2-acetamido-1,4-imino-1,2,4-trideoxy-l-arabinitol LABNAc, a potent pyrrolidine inhibitor of hexosaminidases

Cited by 29 publications

References 45 publications

Design, Synthesis, and Biological Evaluation of Enantiomeric β‐N‐Acetylhexosaminidase Inhibitors LABNAc and DABNAc as Potential Agents against Tay‐Sachs and Sandhoff Disease

Design, Synthesis, and Biological Evaluation of Enantiomeric β‐N‐Acetylhexosaminidase Inhibitors LABNAc and DABNAc as Potential Agents against Tay‐Sachs and Sandhoff Disease

Lysosomal storage of oligosaccharide and glycosphingolipid in imino sugar treated cells

Synthesis of Pyrrolidine Monocyclic Analogues of Pochonicine and Its Stereoisomers: Pursuit of Simplified Structures and Potent β-N-Acetylhexosaminidase Inhibition

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