Alpha-aminoxy acids as building blocks for the oxime and hydroxylamine pseudopeptide links. Application to the synthesis of human elastase inhibitors.

The aminoxy acids NH2-O-(CHR)-H-alpha-CO2H are much more easily obtained in the enantiomerically pure form than the analogous hydrazino acids NH2-NH-CalphaHR-CO2H, and it has been shown that the isosteric amidoxy psi[CO-NH-O] and hydrazide psi[CO-NH-NH] amide surrogates induce two quite similar gamma-like folded structures. An aminoxy acid can also be N-coupled to a peptide aldehyde to give the aldoxime psi[CH=N-O] link or to a peptide ketone to form the ketoxime psi[CR=N-O] link. The former can be further reduced into the hydroxylamine psi[CH2-NH-O] link which gives rise to reduced amidoxy peptides. The structural proper-ties induced by these amide surrogates were studied, using IR and NMR spectroscopy, paying particular attention to the Z/E-isomerism of the oxime link. In order to investigate their inhibitory potency, the three amide surrogates were introduced in the Pro(3)-Val(4) and Val(4)-Ala(5) position of Z-Ala(1)-Ala(2)-Pro(3)-Val(4)-Ala(5)-Ala(6)-NHiPr, a substrate which is cleaved in the Val(4)-Ala(5) position by human leukocyte elastase (HLE). The [Val(4)psi[CO-NH-O]Ala(5)] analogue was still a substrate, while the [Pro(3)psi[CO-NH-O]Val(4)] and [Val(4)psi[CH=N-O]Ala(5)] pseudopeptides acted as HLE competitive inhibitors. Copyright (C) 2003 European Peptide Society and John Wiley Sons, Ltd.