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

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 cyclis...

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Autores principales: Dixon, Mark J., Nathubhai, Amit, Andersen, Ole A., van Aalten, Daan M. F., Eggleston, Ian M.
Formato: Texto
Lenguaje:English
Publicado: Royal Society of Chemistry 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2657367/
https://www.ncbi.nlm.nih.gov/pubmed/19109670
http://dx.doi.org/10.1039/b815077j
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author Dixon, Mark J.
Nathubhai, Amit
Andersen, Ole A.
van Aalten, Daan M. F.
Eggleston, Ian M.
author_facet Dixon, Mark J.
Nathubhai, Amit
Andersen, Ole A.
van Aalten, Daan M. F.
Eggleston, Ian M.
author_sort Dixon, Mark J.
collection PubMed
description 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.
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spelling pubmed-26573672009-03-18 Solid-phase synthesis of cyclic peptide chitinase inhibitors: SAR of the argifin scaffold Dixon, Mark J. Nathubhai, Amit Andersen, Ole A. van Aalten, Daan M. F. Eggleston, Ian M. Org Biomol Chem Chemistry 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. Royal Society of Chemistry 2009-01-21 2008-11-13 /pmc/articles/PMC2657367/ /pubmed/19109670 http://dx.doi.org/10.1039/b815077j Text en This journal is © The Royal Society of Chemistry 2008 http://creativecommons.org/licenses/by-nc/2.0/uk/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Chemistry
Dixon, Mark J.
Nathubhai, Amit
Andersen, Ole A.
van Aalten, Daan M. F.
Eggleston, Ian M.
Solid-phase synthesis of cyclic peptide chitinase inhibitors: SAR of the argifin scaffold
title Solid-phase synthesis of cyclic peptide chitinase inhibitors: SAR of the argifin scaffold
title_full Solid-phase synthesis of cyclic peptide chitinase inhibitors: SAR of the argifin scaffold
title_fullStr Solid-phase synthesis of cyclic peptide chitinase inhibitors: SAR of the argifin scaffold
title_full_unstemmed Solid-phase synthesis of cyclic peptide chitinase inhibitors: SAR of the argifin scaffold
title_short Solid-phase synthesis of cyclic peptide chitinase inhibitors: SAR of the argifin scaffold
title_sort solid-phase synthesis of cyclic peptide chitinase inhibitors: sar of the argifin scaffold
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2657367/
https://www.ncbi.nlm.nih.gov/pubmed/19109670
http://dx.doi.org/10.1039/b815077j
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