title: Stereoselective synthesis of 2-acetamido-1,2-dideoxynojirimycin (DNJNAc) and ureido-DNJNAc derivatives as new hexosaminidase inhibitors.
abstract: 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 a high overall yield is here described. This novel procedure further allowed accessing ureido-DNJNAc 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.
authors.affiliation: Institute for Research in Biomedicine (IRB Barcelona), Baldiri Reixac 10, E-08028 Barcelona, Spain.
authors.forename: Alex
authors.initials: A
authors.lastname: de la Fuente
authors.forename: Teresa
authors.initials: T
authors.lastname: Mena-Barragán
authors.forename: Ronald A
authors.initials: RA
authors.lastname: Farrar-Tobar
authors.forename: Xavier
authors.initials: X
authors.lastname: Verdaguer
authors.forename: José M
authors.initials: JM
authors.lastname: García Fernández
authors.forename: Carmen
authors.initials: C
authors.lastname: Ortiz Mellet
authors.forename: Antoni
authors.initials: A
authors.lastname: Riera
mesh_terms: D017485:1-Deoxynojirimycin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry; D000818:Animals; D002417:Cattle; D060326:Chemistry Techniques, Synthetic; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification
chemical_list: C576450:2-acetamido-1,2-dideoxy-D-gluco-nojirimycin; D000081:Acetamides; D004791:Enzyme Inhibitors; C053655:2-acetamido-1,5-imino-1,2,5-trideoxy-D-glucitol; D017485:1-Deoxynojirimycin; D001619:beta-N-Acetylhexosaminidases