Work

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

Year: 2008

Type: article

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 via derivatisation 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.

Source: Organic & Biomolecular Chemistry

DOI: 10.1039/b815077j

Authors: Mark J. Dixon, Amit Nathubhai, Ole A. Andersen, Daan M. F. van Aalten, Ian M. Eggleston

Institutions: University of Bath, University of Dundee

Language: English

Topic: Chemical Synthesis and Analysis

Subfield: Organic Chemistry

Field: Chemistry

Domain: Physical Sciences

Open Access status: hybrid

Funders: Wellcome Trust, Biotechnology and Biological Sciences Research Council

Awards: Molecular mechanisms of O-GlcNAc signalling., Structure-based design and synthesis of carbohydrate-mimetic peptides as chitinase inhibitors and potential chemotherapeutic agents.