Novel UDP-glycal derivatives as transition state analogue inhibitors of UDP-GlcNAc 2-epimerase.
The "epimerisation" of UDP-GlcNAc to ManNAc, the first step in the biosynthesis of sialic acids, is catalyzed by UDP-GlcNAc 2-epimerase. In this paper we report the synthesis of transition state based inhibitors of this enzyme. To mimic the assumed first transition state of this reaction (TS 1), we designed and synthesized the novel UDP-exo-glycal derivatives 1-4. We also report herein the synthesis of 5 and 6, the first C-glycosidic derivatives of 2-acetamidoglucal, and the synthesis of the ketosides 7 and 8, which were designed as bis-substrate analogue and bis- product analogue, respectively, to mimic the second step of the reaction via the assumed second transition state TS 2.
Stolz
Florian
F
Fachbereich Chemie, Universität Konstanz, Fach M725, D-78457 Konstanz, Germany.
Reiner
Martin
M
Blume
Astrid
A
Reutter
Werner
W
Schmidt
Richard R
RR
D002238:Carbohydrate Epimerases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006595:Hexosamines / Q000737:chemistry; D018716:Molecular Mimicry; D012794:Sialic Acids / Q000737:chemistry; D013237:Stereoisomerism; D014530:Uridine Diphosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry
D004791:Enzyme Inhibitors; D006595:Hexosamines; D012794:Sialic Acids; C019231:2-acetamidoglucal; D014530:Uridine Diphosphate; D002238:Carbohydrate Epimerases; C100033:UDP acetylglucosamine-2-epimerase