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First Synthesis of Argadin: A Nanomolar Inhibitor of Family‐18 Chitinases
Author(s) -
Dixon Mark J.,
Andersen Ole A.,
van Aalten Daan M. F.,
Eggleston Ian M.
Publication year - 2006
Publication title -
european journal of organic chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.825
H-Index - 155
eISSN - 1099-0690
pISSN - 1434-193X
DOI - 10.1002/ejoc.200600599
Subject(s) - chemistry , diastereomer , moiety , stereochemistry , residue (chemistry) , peptide synthesis , peptide , protecting group , natural product , aspergillus fumigatus , side chain , combinatorial chemistry , organic chemistry , biochemistry , alkyl , microbiology and biotechnology , biology , polymer
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 K i = 33 n M . 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)