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

M J Dixon, O A Andersen, D M F van Aalten, I M Eggleston

Research output: Contribution to journalArticlepeer-review

17 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 (ChiBl from Aspergillus fumigatus) with K-i = 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.
Original languageEnglish
Pages (from-to)5002-5006
Number of pages5
JournalEuropean Journal of Organic Chemistry
Volume22
DOIs
Publication statusPublished - 2006

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