Systematic synthesis of bisubstrate-type inhibitors of N-acetylglucosaminyltransferases

Chemistry : a European Journal
Shinya HanashimaYukishige Ito

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 beta-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 ...Continue Reading

References

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Citations

Jan 30, 2016·Glycobiology·Pavel JanošJaroslav Koca
Nov 26, 2008·Bioorganic & Medicinal Chemistry·Kazusa NishiyamaSusumu Kobayashi
Sep 20, 2012·Biochemical Society Transactions·Tracey M Gloster
May 3, 2016·Biomolecules·Yasuhiko Kizuka, Naoyuki Taniguchi
Aug 21, 2014·Bioorganic & Medicinal Chemistry Letters·Shinya HanashimaYoshiki Yamaguchi
Aug 31, 2007·Chemical Communications : Chem Comm·Shino ManabeYukishige Ito
May 18, 2010·Chemical Communications : Chem Comm·Marek FiglusRichard C Hartley
Nov 17, 2009·Journal of Enzyme Inhibition and Medicinal Chemistry·P B Le CalvezM E Migaud
May 1, 2019·Medical Oncology·Ling TangXiang Chen
Aug 25, 2018·Nature Communications·Masamichi NagaeYoshiki Yamaguchi
Jan 16, 2020·International Journal of Molecular Sciences·Masamichi NagaeYasuhiko Kizuka
Sep 6, 2020·Biochimica Et Biophysica Acta. General Subjects·Tetsuya HirataYasuhiko Kizuka
Mar 29, 2011·ACS Combinatorial Science·Marek FiglusRichard C Hartley

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