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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...
Autores principales: | , , , , |
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Formato: | Texto |
Lenguaje: | English |
Publicado: |
Royal Society of Chemistry
2009
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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. |
format | Text |
id | pubmed-2657367 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2009 |
publisher | Royal Society of Chemistry |
record_format | MEDLINE/PubMed |
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
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title_full | Solid-phase synthesis of cyclic peptide chitinase inhibitors: SAR of the argifin scaffold
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title_fullStr | Solid-phase synthesis of cyclic peptide chitinase inhibitors: SAR of the argifin scaffold
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title_full_unstemmed | Solid-phase synthesis of cyclic peptide chitinase inhibitors: SAR of the argifin scaffold
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title_short | Solid-phase synthesis of cyclic peptide chitinase inhibitors: SAR of the argifin scaffold
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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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