TY - JOUR T1 - Solid-phase synthesis of cyclic peptide chitinase inhibitors T2 - SAR of the argifin scaffold A1 - Dixon,Mark J. A1 - Nathubhai,Amit A1 - Andersen,Ole A. A1 - van Aalten,Daan M. F. A1 - Eggleston,Ian M. AU - Dixon,Mark J. AU - Nathubhai,Amit AU - Andersen,Ole A. AU - van Aalten,Daan M. F. AU - Eggleston,Ian M. PY - 2009 Y1 - 2009 N2 -

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.

AB -

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.

KW - Acidic mammalian chitinase KW - Butyloxycarbonyl group KW - Efficient synthesis KW - Product KW - Chitotriosidase KW - Removal KW - Cell KW - Parasite KW - Collagen KW - Analogs U2 - 10.1039/b815077j DO - 10.1039/b815077j M1 - Article JO - Organic and Biomolecular Chemistry JF - Organic and Biomolecular Chemistry SN - 1477-0520 IS - 2 VL - 7 SP - 259 EP - 268 ER -