INHIBITION OF HUMAN-LEUKOCYTE ELASTASE BY FUNCTIONALIZED N-ARYL AZETIDIN-2-ONES - SUBSTITUENT EFFECTS AT C-3 AND BENZYLIC POSITIONS

A series of functionalized N-aryl azetidin-2-ones with a latent alkyla ting group was prepared by a flexible four-step synthesis. They met cr iteria expected for a suicide-type inactivation of human leukocyte ela stase (HLE) and porcine pancreatic elastase (PPE), with no inactivatio n of trypsin- and chymotrypsin-like proteases. The inhibition potency was dependent on the halogen substituents at C-3 (F, F; Cl, Cl; Br, Br ) and the nature and the position relative to nitrogen of the latent b enzylic leaving group (F, Cl, Br). Better inactivations of HLE compare d with PPE were observed with azetidinones gem-disubstituted by Cl and Br rather than by F. Their protio analogs, which are devoid of the la tent quinoniminium methide electrophile, behave as simple substrates o f elastases.