Solid-phase synthesis of cyclic peptide chitinase inhibitors: SAR of the argifin scaffold

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

    Research output: Contribution to journalArticle

    28 Citations (Scopus)

    Abstract

    A new, highly efficient, all-solid-phase synthesis of argifin, a natural product cyclic pentapeptide chitinase inhibitor, is reported. The synthesis features attachment of an orthogonally protected Asp residue to the solid support and assembly of the linear peptide chain by Fmoc SPPS prior to cyclisation and side-chain manipulation on-resin. Introduction of the key N-methyl carbamoyl-substituted Arg side chain is achieved via derivatisation of a selectively protected Orn residue, prior to cleavage from the resin and side-chain deprotection. A severe aspartimide side-reaction observed upon final deprotection is circumvented by the use of a novel aqueous acidolysis procedure. The. exibility of the synthesis is demonstrated by the preparation of a series of argifin analogues designed from the X-ray structure of the natural product in complex with a representative family 18 chitinase.

    Original languageEnglish
    Pages (from-to)259-268
    Number of pages10
    JournalOrganic and Biomolecular Chemistry
    Volume7
    Issue number2
    Early online date13 Nov 2008
    DOIs
    Publication statusPublished - 2009

    Keywords

    • Acidic mammalian chitinase
    • Butyloxycarbonyl group
    • Efficient synthesis
    • Product
    • Chitotriosidase
    • Removal
    • Cell
    • Parasite
    • Collagen
    • Analogs

    Cite this