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Synthesis and evaluation of potential inhibitors of chondroitin AC lyase from Flavobacterium heparinum

TitleSynthesis and evaluation of potential inhibitors of chondroitin AC lyase from Flavobacterium heparinum
Publication TypeJournal Article
Year of Publication2002
AuthorsRye, CS, Withers, SG
JournalJOURNAL OF ORGANIC CHEMISTRY
Volume67
Pagination4505-4512
Date PublishedJUN 28
ISSN0022-3263
Abstract

Chondroitin AC lyase from Flavobacterium heparinum degrades chondroitin sulfate glycosamino-glycans via an elimination mechanism, resulting in disaccharides or oligosaccharides with Delta4,5-unsaturated uronic acid residues at their nonreducing end. The syntheses and testing of two potential inhibitors of this lyase are described. Methyl O-(2-acetamido-2-deoxy-beta-D-galactopyranosyl)(1–>4)-alpha-L-threo-hex -4-enopyranoside, 1, has the trigonal geometry at C5 of the uronic acid moiety expected at the transition state, yet retains the ``leaving group{''} sugar moiety. Surprisingly, compound 1 showed no inhibition of the enzyme. The novel 5-nitro sugar, phenyl (5S)-5-nitro-beta-D-xylopyranoside, 2, is a monosaccharide nitro analogue of the natural substrate, with C5 being a carbon acid of pK(a) 8.8. The rate of reprotonation of the anion generated at this center is sufficiently low that the anion of 2 can be used directly in initial steady-state velocity measurements without significant interference from the conjugate carbon acid. The anion of compound 2 was found to be a competitive inhibitor with a K-i value of 5 mM, whereas the conjugate acid had a K-i value of 35 mM.

DOI10.1021/jo020089m