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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. exibility 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.
|Number of pages||10|
|Journal||Organic and Biomolecular Chemistry|
|Early online date||13 Nov 2008|
|Publication status||Published - 2009|
- Acidic mammalian chitinase
- Butyloxycarbonyl group
- Efficient synthesis
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- 1 Finished
Aref#d: 21318. Molecular Mechanisms of O-GlcNAc Signalling (Senior Fellowship Renewal)
1/06/09 → 29/02/16