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Functionalized N ‐aryl azetidinones as novel mechanism‐based inhibitors of neutrophil elastase
Author(s) -
Wakselman Michel,
Joyeau Roger,
Kobaiter Randa,
Boggetto Nicole,
Vergely Isabelle,
Maillard Jean,
Okochi Veronica,
Montagne Jean-Jacques,
Reboud-Ravaux Michèle
Publication year - 1991
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/0014-5793(91)80517-7
Subject(s) - chemistry , elastase , enzyme , pancreatic elastase , nucleophile , stereochemistry , elastin , biochemistry , biology , catalysis , genetics
A functionalized N ‐aryl azetidinone has been shown to inactive human leukocyte elastase (HLE) and porcine pancreatic elastase (PPE) by an enzyme‐mediated process. The inactivation is characterized by the following kinetic constants at pH 8.0 and 37°C: k max =0.035 s −1 , K 1 =1.2 × 10 −4 M for HLE, 0.08 s −1 and 2.7 × 10 −4 M for PPE, respectively. Two parent molecules devoid of the latent leaving group failed to inactive HLE and PPE and behaved as substrates of these enzymes. A suicide mechanism involving the formation of an acyl‐enzyme and the simultaneous unmasking of a latent quinonimmonium methide ion which irreversibly reacts with an active site nucleophile. Moreover, the inhibitor is still effective at inhibiting elastase preabsorbed onto elastin.