A divergent synthesis of 2-acyl derivatives of PUGNAc yields selective inhibitors of O-GlcNAcase.
A divergent route facilitating the rapid synthesis of a series of O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino N-phenylcarbamate (PUGNAc)-based inhibitors, bearing different N-acyl groups has been developed. All compounds of this series are inhibitors of both human O-GlcNAcase and human beta-hexosaminidase, yet some effectively exploit differences between the active site architectures of these two human enzymes which render them selective for O-GlcNAcase. Such inhibitors may be valuable tools in dissecting the role of the O-GlcNAc post-translational modification at the cellular and organismal level since these compounds may have different pharmacokinetic properties when compared to other inhibitors of beta-N-acetyl-glucosaminidases.
Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, BC, Canada V5A 1S6.
Keith A
KA
Stubbs
Nelson
N
Zhang
David J
DJ
Vocadlo
D000117:Acetylglucosamine / Q000031:analogs & derivatives* / Q000737:chemistry; D001671:Biochemistry / Q000379:methods*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D010091:Oximes / Q000737:chemistry*; D048448:Phenylcarbamates / Q000737:chemistry*; D013329:Structure-Activity Relationship; D001619:beta-N-Acetylhexosaminidases / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D010091:Oximes; D048448:Phenylcarbamates; C068836:N-acetylglucosaminono-1,5-lactone O-(phenylcarbamoyl)oxime; C110628:hexosaminidase C; D001619:beta-N-Acetylhexosaminidases; D000117:Acetylglucosamine