Issue 2, 2009

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

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 viaderivatisation 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 flexibility 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.

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

Supplementary files

Article information

Article type
Paper
Submitted
29 Aug 2008
Accepted
06 Oct 2008
First published
13 Nov 2008
This article is Open Access

Org. Biomol. Chem., 2009,7, 259-268

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

M. J. Dixon, A. Nathubhai, O. A. Andersen, D. M. F. van Aalten and I. M. Eggleston, Org. Biomol. Chem., 2009, 7, 259 DOI: 10.1039/B815077J

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