title: 3-Hydroxyazetidine carboxylic acids: non-proteinogenic amino acids for medicinal chemists.
abstract: The formation from D-glucose of both enantiomers of 2,4-dideoxy-2,4-iminoribonic acid is the first chemical synthesis of unprotected 3-hydroxyazetidine carboxylic acids. The long-term stability of 3-hydroxyazetidine amides is established at acidic and neutral pH and implies their value as non-proteinogenic amino acid components of peptides, providing medicinal chemists with a new class of peptide isosteres. The structure of N,3-O-dibenzyl-2,4-dideoxy-2,4-imino-D-ribonic acid was established by X-ray crystallographic analysis. An N-methylazetidine amide derivative is a specific inhibitor of β-hexosaminidases at the micromolar level, and is only the second example of potent inhibition of any glycosidase by an amide of a sugar amino acid related to an iminosugar.
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Mansfield Road, Oxford, OX1 3TA, UK.
authors.forename: Andreas F G
authors.initials: AF
authors.lastname: Glawar
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Jenkinson
authors.forename: Amber L
authors.initials: AL
authors.lastname: Thompson
authors.forename: Shinpei
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.forename: Terry D
authors.initials: TD
authors.lastname: Butters
authors.forename: George W J
authors.initials: GW
authors.lastname: Fleet
mesh_terms: D000577:Amides / Q000737:chemistry; D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D001383:Azetidinecarboxylic Acid / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D006596:Hexosaminidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D050111:Imino Sugars / Q000737:chemistry; D008968:Molecular Conformation; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000596:Amino Acids; D001384:Azetidines; D004791:Enzyme Inhibitors; D050111:Imino Sugars; D001383:Azetidinecarboxylic Acid; D006596:Hexosaminidases