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

J Pept Sci. 2003 May;9(5):282-99. doi: 10.1002/psc.452.

Abstract

The aminoxy acids NH2-O-C(alpha)HR-CO2H are much more easily obtained in the enantiomerically pure form than the analogous hydrazino acids NH2-NH-C(alpha)HR-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 properties 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 Pro3-Val4 and Val4-Ala5 position of Z-Ala1-Ala2-Pro3-Val4-Ala5-Ala6-NHiPr, a substrate which is cleaved in the Val4-Ala5 position by human leukocyte elastase (HLE). The [Val4psi[CO-NH-O]Ala5] analogue was still a substrate, while the [Pro3psi[CO-NH-O]Val4] and [Val4psi[CH = N-O]Ala5] pseudopeptides acted as HLE competitive inhibitors.

MeSH terms

  • Aldehydes / chemical synthesis
  • Amides / chemistry
  • Amino Acid Sequence
  • Amino Acids / chemistry*
  • Dimethyl Sulfoxide / chemistry
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Humans
  • Hydroxylamine / chemistry*
  • Ketones / chemical synthesis
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology
  • Oximes / chemical synthesis*
  • Pancreatic Elastase / antagonists & inhibitors*
  • Protein Conformation

Substances

  • Aldehydes
  • Amides
  • Amino Acids
  • Enzyme Inhibitors
  • Ketones
  • Oligopeptides
  • Oximes
  • Hydroxylamine
  • Pancreatic Elastase
  • Dimethyl Sulfoxide