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

Reference:

Dixon, M. J., Andersen, O. A., van Aalten, D. M. F. and Eggleston, I. M., 2006. First synthesis of argadin: A nanomolar inhibitor of family-18 chitinases. European Journal of Organic Chemistry, 22, pp. 5002-5006.

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Official URL:

http://dx.doi.org/10.1002/ejoc.200600599

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.

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