Systematic synthesis of bisubstrate-type inhibitors of TV- acetylglucosaminyltransferases

Shinya Hanashima, Kei Ichiro Inamori, Shino Manabe, Naoyuki Taniguchi, Yukishige Ito

Research output: Contribution to journalArticlepeer-review

31 Citations (Scopus)

Abstract

Bisubstrate-type inhibitors for N-acetylglucosaminyltransferase (GnT)-V and -IX were designed and synthesized. These compounds carry both an acceptor trisaccaride and an UDP-GlcNAc component tethered by a linker of variable length. The acceptor trisaccharide unit was constructed using a combination of a polymer support and a resin capture-release strategy. Namely, starting with a β-mannoside bound to low molecular weight monomethyl PEG (MPEG), successive glycosylations with donors having chloroacetyl group produced the trisaccharide, which was subjected to the capture-release purification using cysteine loaded resin. UDP-GlcNAc units carrying phosphate moieties were separately synthesized from the bromoacetamide-containing glucosamine derivative. Ligation between the acceptor thiol and each alkyl bromide on the donor unit readily proceeded, and produced the coupling product. The introduction of the UMP component gave target compounds. All of the synthesized compounds had significant activities to GnT-V and -IX. Their potencies were dependent upon the linkers length. GnT-IX was more sensitive to these inhibitors and optimum linker length was clearly different between these GnTs. The most potent inhibitor of GnT-V had Ki = 18.3 μM, while that of GnT-IX had Ki = 4.7 μM.

Original languageEnglish
Pages (from-to)3449-3462
Number of pages14
JournalChemistry - A European Journal
Volume12
Issue number13
DOIs
Publication statusPublished - 2006 Apr 24
Externally publishedYes

Keywords

  • Glycoproteins glycosylation
  • Glycosyltransferase
  • Inhibitors
  • Solid-phase synthesis

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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