An efficient and versatile synthesis of GlcNAcstatins-potent and selective O-GlcNAcase inhibitors built on the tetrahydroimidazo[1,2-a]pyridine scaffold

Vladimir S. Borodkin, Daan M. F. van Aalten

    Research output: Contribution to journalArticlepeer-review

    6 Citations (Scopus)

    Abstract

    We report a novel approach to the synthesis of GlcNAcstatins members of an emerging family of potent and selective inhibitors of peptidyl O-GlcNAc hydrolase build upon tetrahydroimidazo[1,2-a]pyridine scaffold. Making use of a streamlined synthetic sequence featuring de novo synthesis of imidazoles from glyoxal, ammonia and aldehydes, a properly functionalised linear GlcNAcstatin precursor has been efficiently prepared starting from methyl 3,4-O-(2',3'-dimethoxybutane-2',3'-diyl)-alpha-D-mannopyranoside. Subsequent ring closure of the linear precursor in an intramolecular S(N)2 process furnished the key fused D-mannose-imidazole GlcNAcstatin precursor in excellent yield. Finally, a sequence of transformations of this key intermediate granted expeditious access to a variety of the target compounds bearing a C(2)phenethyl group and a range of N(8) acyl substituents. The versatility of the new approach stems from an appropriate choice of a set of acid labile permanent protecting groups on the monosaccharide starting material. Application was demonstrated by the synthesis of GlcNAcstatins containing polyunsaturated and thiol-containing amido substituents. (C) 2010 Elsevier Ltd. All rights reserved.

    Original languageEnglish
    Pages (from-to)7838-7849
    Number of pages12
    JournalTetrahedron
    Volume66
    Issue number39
    Early online date22 Jul 2010
    DOIs
    Publication statusPublished - 25 Sep 2010

    Keywords

    • Beta-N-acetylglucosaminidase
    • Glycosidase inhibitors
    • D-glucosaminidase
    • Nagstatin analogs
    • In vivo
    • Mechanism
    • Tetrahydroimidazopyridines
    • Glycosylation
    • Configuration
    • Derivatives

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