First synthesis of argadin: a nanomolar inhibitor of family-18 chitinases

Mark J. Dixon, Ole A. Andersen, Daan M. F. van Aalten, Ian M. Eggleston

    Research output: Contribution to journalArticlepeer-review

    16 Citations (Scopus)

    Abstract

    The first synthesis of the cyclic peptide natural product, argadin is reported. Use of a solid-phase approach featuring side-chain resin attachment through histidine and a novel protecting group strategy allows rapid and efficient access to the argadin backbone, whereupon the unusual 3-amino-5-hydroxy-2-pyrrolidone moiety of the peptide is introduced by oxidative cyclisation of a homoserine residue. Argadin is shown to exist as a 5:1 mixture of diastereoisomers at the 5-hydroxy centre of the pyrrolidone ring, and inhibits a representative family-18 chitinase (ChiB1 from Aspergillus fumigatus) with Ki = 33 nM. The high-resolution X-ray crystal structure of synthetic argadin in complex with the same enzyme shows the binding of a single diastereoisomer as previously observed with the authentic natural product. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006)

    Original languageEnglish
    Pages (from-to)5002-5006
    Number of pages5
    JournalEuropean Journal of Organic Chemistry
    Volume2006
    Issue number22
    DOIs
    Publication statusPublished - 2006

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