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

Dixon, M.J., Nathubhai, Amit, Andersen, O.A., van Aalten, D.M.F. and Eggleston, I.M. (2008) Solid-phase synthesis of cyclic peptide chitinase inhibitors: SAR of the argifin scaffold. Organic & Biomolecular Chemistry, 7. pp. 259-268. ISSN 1477-0520

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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.

Item Type: Article
Subjects: Sciences > Chemistry
Divisions: Health Sciences and Wellbeing Beacon > Drug Discovery and Application Workstream
Faculty of Health Sciences and Wellbeing
Depositing User: Amit Nathubhai
Date Deposited: 10 Aug 2018 12:38
Last Modified: 10 Aug 2018 12:38
URI: http://sure.sunderland.ac.uk/id/eprint/9794

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