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-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.
Vanderesse
Regis
R
LCPM, UMR CNRS-INPL 7568, ENSIC-INPL BP 451, 54001 Nancy, France. Regis.Vanderesse@ensic.inpl-nancy.fr
Thevenet
Laurent
L
Marraud
Michel
M
Boggetto
Nicole
N
Reboud
Michele
M
Corbier
Catherine
C
D000447:Aldehydes / Q000138:chemical synthesis; D000577:Amides / Q000737:chemistry; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry*; D004121:Dimethyl Sulfoxide / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D019811:Hydroxylamine / Q000737:chemistry*; D007659:Ketones / Q000138:chemical synthesis; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010091:Oximes / Q000138:chemical synthesis*; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors*; D011487:Protein Conformation
D000447:Aldehydes; D000577:Amides; D000596:Amino Acids; D004791:Enzyme Inhibitors; D007659:Ketones; D009842:Oligopeptides; D010091:Oximes; D019811:Hydroxylamine; D010196:Pancreatic Elastase; D004121:Dimethyl Sulfoxide