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

Dixon MJ, Nathubhai A, Andersen OA, van Aalten DM, Eggleston IM - Org. Biomol. Chem. (2008)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA27AY, UK.

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.

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Synthetic approaches to argifin. Path A: All-solid-phase approach. Path B: Previous combined solid-phase–solution approach. (Path B requires HPLC purification prior to the final acylation stage).20 For both synthetic routes, P5 corresponds to temporary N(α)-protection. For Path A, P1, P3, P4 correspond to side-chain protection, P2 to the solid support. For Path B, P1, P2, P3 correspond to side-chain protection, P4 to the solid support.
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sch1: Synthetic approaches to argifin. Path A: All-solid-phase approach. Path B: Previous combined solid-phase–solution approach. (Path B requires HPLC purification prior to the final acylation stage).20 For both synthetic routes, P5 corresponds to temporary N(α)-protection. For Path A, P1, P3, P4 correspond to side-chain protection, P2 to the solid support. For Path B, P1, P2, P3 correspond to side-chain protection, P4 to the solid support.

Mentions: In our original synthesis of 3,20 the key N-methyl carbamoyl modification of the Arg residue was effected in solution as the final step (Scheme 1). However, acidolytic deprotection of the preceding Arg-containing cyclic peptide precursor proved to be problematic, necessitating a time-consuming HPLC purification at this stage of the synthesis and a consequently reduced overall yield. In order to improve the efficiency of production of 3, and develop SAR around the argifin scaffold, we have therefore developed a new synthesis of 3 and analogues based upon an all-solid-phase approach, in the process identifying a significant side reaction in our previous synthesis, that is eliminated now via a novel side-chain deprotection procedure. The flexibility of the synthetic strategy is demonstrated by the preparation of a series of compounds inspired by the X-ray structure of 3 in complex22 with a representative family 18 chitinase (chitinase B1 from Aspergillus fumigatus, AfChiB1).


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

Dixon MJ, Nathubhai A, Andersen OA, van Aalten DM, Eggleston IM - Org. Biomol. Chem. (2008)

Synthetic approaches to argifin. Path A: All-solid-phase approach. Path B: Previous combined solid-phase–solution approach. (Path B requires HPLC purification prior to the final acylation stage).20 For both synthetic routes, P5 corresponds to temporary N(α)-protection. For Path A, P1, P3, P4 correspond to side-chain protection, P2 to the solid support. For Path B, P1, P2, P3 correspond to side-chain protection, P4 to the solid support.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2657367&req=5

sch1: Synthetic approaches to argifin. Path A: All-solid-phase approach. Path B: Previous combined solid-phase–solution approach. (Path B requires HPLC purification prior to the final acylation stage).20 For both synthetic routes, P5 corresponds to temporary N(α)-protection. For Path A, P1, P3, P4 correspond to side-chain protection, P2 to the solid support. For Path B, P1, P2, P3 correspond to side-chain protection, P4 to the solid support.
Mentions: In our original synthesis of 3,20 the key N-methyl carbamoyl modification of the Arg residue was effected in solution as the final step (Scheme 1). However, acidolytic deprotection of the preceding Arg-containing cyclic peptide precursor proved to be problematic, necessitating a time-consuming HPLC purification at this stage of the synthesis and a consequently reduced overall yield. In order to improve the efficiency of production of 3, and develop SAR around the argifin scaffold, we have therefore developed a new synthesis of 3 and analogues based upon an all-solid-phase approach, in the process identifying a significant side reaction in our previous synthesis, that is eliminated now via a novel side-chain deprotection procedure. The flexibility of the synthetic strategy is demonstrated by the preparation of a series of compounds inspired by the X-ray structure of 3 in complex22 with a representative family 18 chitinase (chitinase B1 from Aspergillus fumigatus, AfChiB1).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA27AY, UK.

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.

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