First Synthesis of Argadin: A Nanomolar Inhibitor of Family‐18 Chitinases

Abstract

AbstractThe 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)