Scalable Syntheses of Both Enantiomers of DNJNAc and DGJNAc from Glucuronolactone: The Effect of <i>N</i>‐Alkylation on Hexosaminidase Inhibition

Glawar, Andreas F. G.; Best, Daniel; Ayers, Benjamin James; Miyauchi, Saori; Nakagawa, Shigeaki; Aguilar‐Moncayo, Matilde; Fernández, José Manuel Garcı́a; Mellet, Carmen Ortiz; Crabtree, Elizabeth V.; Butters, Terry D.; Wilson, Francis X.; Kato, Atsushi; Fleet, George W. J.

doi:10.1002/chem.201200110

Cited by 44 publications

(43 citation statements)

References 88 publications

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“…25 Benzylation of the lyxo-pentitols 13D and 13L transforms α-D-galactosidase inhibitors into potent inhibitors of α-L-rhamnosidase. 35 Benzylation of the 2-N-acetylamino-1,2,4-trideoxy-1,4-iminopentitols under investigation here in general causes an increase in the potency of HexNAcase inhibition ( Table 2); however the xylo-NH 20D [K i = 0.29 μM] is a stronger inhibitor of the HL-60 derived enzyme than is the corresponding NBn derivative 21D [K i = 0.54 μM].…”

Section: Biological Evaluationmentioning

confidence: 99%

“…13,14 Although hundreds of iminosugars 15 is the only known potent inhibitor of α-GalNAcases but is also a good inhibitor of HexNAcases. 25 Both the amides of hydroxylated pipecolic 8 26 and azetidine 9 27 carboxylic acids are potent inhibitors of HexNAcases. ADMDP (1-acetamido-1,2,5-trideoxy-2,5-imino-D-mannitol) 10 28,29 is a rare example of a potent pyrrolidine HexNAcase inhibitor.…”

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confidence: 99%

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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

et al. 2014

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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-benzyl derivatives are better inhibitors than the parent compounds. Both XYLNAc and LABNAc are potent inhibitors against HexNAcases. None of the compounds show any inhibition of α-GalNAcase.

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Section: Biological Evaluationmentioning

confidence: 99%

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confidence: 99%

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

et al. 2014

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“…Some are very potent with K i values in the μM to nM range, most of which exhibit almost no selectivity toward function-specific β-GlcNAcases. Representative examples include nagstatin18, PUGNAc19, NAG-thiazoline20, GlcNAcstatinA/B21, pochonicine2223, DNJNAc2425 and other iminocyclitols26272829. The carbohydrate-based TMG-chitotriomycin is the first reported highly-selective inhibitor against chitinolytic β-GlcNAcases from bacteria, fungi and insects, but it is not active toward glycoconjugate-lytic β-GlcNAcases from plant and human3031.…”

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A crystal structure-guided rational design switching non-carbohydrate inhibitors' specificity between two β-GlcNAcase homologs

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Zhou

et al. 2014

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Selective inhibition of function-specific β-GlcNAcase has great potential in terms of drug design and biological research. The symmetrical bis-naphthalimide M-31850 was previously obtained by screening for specificity against human glycoconjugate-lytic β-GlcNAcase. Using protein-ligand co-crystallization and molecular docking, we designed an unsymmetrical dyad of naphthalimide and thiadiazole, Q2, that changes naphthalimide specificity from against a human glycoconjugate-lytic β-GlcNAcase to against insect and bacterial chitinolytic β-GlcNAcases. The crystallographic and in silico studies reveal that the naphthalimide ring can be utilized to bind different parts of these enzyme homologs, providing a new starting point to design specific inhibitors. Moreover, Q2-induced closure of the substrate binding pocket is the structural basis for its 13-fold increment in inhibitory potency. Q2 is the first non-carbohydrate inhibitor against chitinolytic β-GlcNAcases. This study provides a useful example of structure-based rationally designed inhibitors as potential pharmaceuticals or pesticides.

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“…The spectroscopic data of this compound were consistent with previously reported data. 18 The total synthesis of DNJNAc (4) from 11 was thus accomplished in 10 synthetic steps achieving a 23% overall yield. Although some 3-acetamido iminosugar derivatives have been reported we could not find precedents of evaluation of their properties as glycosidase inhibitors.…”

Section: Resultsmentioning

confidence: 99%

Stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc) and ureido-DNJNAc derivatives as new hexosaminidase inhibitors

et al. 2015

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2-Acetamido-1,2-dideoxyiminosugars are selective and potent inhibitors of hexosaminidases and therefore show high therapeutic potential for the treatment of various diseases, including several lysosomal storage disorders. A stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc), the iminosugar analog of N-acetylglucosamine, with high overall yield is here described. This novel procedure further allowed accessing ureidoDNJNAc conjugates through derivatization of the endocyclic amine on a key pivotal intermediate. Remarkably, some of the ureido-DNJNAc representatives behaved as potent and selective inhibitors of β-hexosaminidases, including the human enzyme, being the first examples of neutral sp 2 -iminosugar-type inhibitors reported for these enzymes. Moreover, the amphiphilic character of the new ureido-DNJNAc is expected to confer better drug-like properties.

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Scalable Syntheses of Both Enantiomers of DNJNAc and DGJNAc from Glucuronolactone: The Effect of N‐Alkylation on Hexosaminidase Inhibition

Abstract: Splitting water: Oxygen‐permeable perovskite hollow‐fiber membranes are used to produce hydrogen and synthesis gas from water and methane (see picture). The process yields valuable compounds, and provides insight into the interplay of catalysis and separation in a membrane reactor.

Cited by 44 publications

References 88 publications

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

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

A crystal structure-guided rational design switching non-carbohydrate inhibitors' specificity between two β-GlcNAcase homologs

Stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc) and ureido-DNJNAc derivatives as new hexosaminidase inhibitors

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