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.
In: Organic and Biomolecular Chemistry, Vol. 7, No. 2, 2009, p. 259-268.Research output: Contribution to journal › Article
}
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 - <p>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.</p>
AB - <p>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.</p>
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 -