title: Nine of 16 stereoisomeric polyhydroxylated proline amides are potent β-N-acetylhexosaminidase inhibitors.
abstract: All 16 stereoisomeric N-methyl 5-(hydroxymethyl)-3,4-dihydroxyproline amides have been synthesized from lactones accessible from the enantiomers of glucuronolactone. Nine stereoisomers, including all eight with a (3R)-hydroxyl configuration, are low to submicromolar inhibitors of β-N-acetylhexosaminidases. A structural correlation between the proline amides is found with the ADMDP-acetamide analogues bearing an acetamidomethylpyrrolidine motif. The proline amides are generally more potent than their ADMDP-acetamide equivalents. β-N-Acetylhexosaminidase inhibition by an azetidine ADMDP-acetamide analogue is compared to an azetidine carboxylic acid amide. None of the amides are good α-N-acetylgalactosaminidase inhibitors.
authors.affiliation: Chemistry Research Laboratory, Department of Chemistry, University of Oxford , Mansfield Road, Oxford OX1 3TA, U.K.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Ayers
authors.forename: Andreas F G
authors.initials: AF
authors.lastname: Glawar
authors.forename: R Fernando
authors.initials: RF
authors.lastname: Martínez
authors.forename: Nigel
authors.initials: N
authors.lastname: Ngo
authors.forename: Zilei
authors.initials: Z
authors.lastname: Liu
authors.forename: George W J
authors.initials: GW
authors.lastname: Fleet
authors.forename: Terry D
authors.initials: TD
authors.lastname: Butters
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Nash
authors.forename: Chu-Yi
authors.initials: CY
authors.lastname: Yu
authors.forename: Mark R
authors.initials: MR
authors.lastname: Wormald
authors.forename: Shinpei
authors.initials: S
authors.lastname: Nakagawa
authors.forename: Isao
authors.initials: I
authors.lastname: Adachi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kato
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Jenkinson
mesh_terms: D000081:Acetamides / Q000737:chemistry*; D000577:Amides / Q000737:chemistry*; D001383:Azetidinecarboxylic Acid / Q000737:chemistry*; D007700:Kinetics; D011392:Proline / Q000031:analogs & derivatives* / Q000737:chemistry*; D013237:Stereoisomerism; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors* / Q000737:chemistry
chemical_list: D000081:Acetamides; D000577:Amides; D001383:Azetidinecarboxylic Acid; C030686:acetamide; D011392:Proline; D001619:beta-N-Acetylhexosaminidases