{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T09:43:30Z","timestamp":1791279810523,"version":"4.1.0"},"reference-count":77,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2009,1,14]],"date-time":"2009-01-14T00:00:00Z","timestamp":1231891200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2009,3,16]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:bold>Combating glycolipid storage disorders<\/jats:bold>: LABNAc was prepared in an efficient 11\u2010step procedure from <jats:sc>D<\/jats:sc>\u2010lyxonolactone. The enantiomer DABNAc was also prepared from <jats:sc>L<\/jats:sc>\u2010lyxonolactone. Preliminary cellular studies indicate that these compounds may find utility as chemical chaperones for the treatment of Tay\u2010Sachs and Sandhoff diseases.<jats:boxed-text content-type=\"graphic\" position=\"anchor\"><jats:graphic xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" mimetype=\"image\/gif\" position=\"anchor\" specific-use=\"enlarged-web-image\" xlink:href=\"graphic\/mcontent.gif\"><jats:alt-text>magnified image<\/jats:alt-text><\/jats:graphic><\/jats:boxed-text><\/jats:p><jats:p><jats:italic>N<\/jats:italic>\u2010Acetylhexosaminidases 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\u2010Sachs and Sandhoff diseases. One promising therapy for these diseases involves the use of \u03b2\u2010<jats:italic>N<\/jats:italic>\u2010acetylhexosaminidase inhibitors as chemical chaperones to enhance the enzyme activity above sub\u2010critical levels. Herein we describe the synthesis and biological evaluation of a potent inhibitor, 2\u2010acetamido\u20101,4\u2010imino\u20101,2,4\u2010trideoxy\u2010<jats:sc>L<\/jats:sc>\u2010arabinitol (LABNAc), in a high\u2010yielding 11\u2010step procedure from <jats:sc>D<\/jats:sc>\u2010lyxonolactone. The <jats:italic>N<\/jats:italic>\u2010benzyl and <jats:italic>N<\/jats:italic>\u2010butyl analogues were also prepared and found to be potent inhibitors. The enantiomers DABNAc and <jats:italic>N<\/jats:italic>Bn\u2010DABNAc were synthesised from <jats:sc>L<\/jats:sc>\u2010lyxonolactone, and were also evaluated. The <jats:sc>L<\/jats:sc>\u2010iminosugar LABNAc and its derivatives were found to be potent noncompetitive inhibitors of some \u03b2\u2010<jats:italic>N<\/jats:italic>\u2010acetylhexosaminidases, while the <jats:sc>D<\/jats:sc>\u2010iminosugar DABNAc and its derivatives were found to be weaker competitive inhibitors. These results support previous work postulating that <jats:sc>D<\/jats:sc>\u2010iminosugar mimics inhibit <jats:sc>D<\/jats:sc>\u2010glycohydrolases competitively, and that their corresponding <jats:sc>L<\/jats:sc>\u2010enantiomers 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\u2010based studies suggest that <jats:italic>N<\/jats:italic>Bn\u2010LABNAc can act as a chemical chaperone to enhance the deficient enzyme's activity to levels that may cause a positive pharmacological effect. LABNAc, <jats:italic>N<\/jats:italic>Bn\u2010LABNAc, and <jats:italic>N<\/jats:italic>Bu\u2010LABNAc are potent and selective inhibitors of \u03b2\u2010<jats:italic>N<\/jats:italic>\u2010acetylhexosaminidase and may be useful as therapeutic agents for treating adult Tay\u2010Sachs and Sandhoff diseases.<\/jats:p>","DOI":"10.1002\/cmdc.200800350","type":"journal-article","created":{"date-parts":[[2009,1,14]],"date-time":"2009-01-14T07:57:02Z","timestamp":1231919822000},"page":"378-392","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":65,"title":["Design, Synthesis, and Biological Evaluation of Enantiomeric \u03b2\u2010<i>N<\/i>\u2010Acetylhexosaminidase Inhibitors LABNAc and DABNAc as Potential Agents against Tay\u2010Sachs and Sandhoff Disease"],"prefix":"10.1002","volume":"4","author":[{"given":"J.\u2005S. 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