title: beta-Lactam derivatives as enzyme inhibitors: 1-peptidyl derivatives of 4-phenylazetidin-2-one as inhibitors of elastase and papain.
abstract: N-Peptidyl substituted azetidin-2-ones were synthesized and evaluated as inhibitors of the serine protease elastase, and the cysteine protease papain. All compounds were synthesized from 4-phenylazetidin-2-one, either from the racemate or from the pure enantiomers. The (S)-enantiomer was prepared by enantioselective synthesis from (S)-beta-phenyl-beta-alanine, while the (R)-enantiomer was obtained by enzymatic resolution with alpha-chymotrypsin. N-Alkylation with bromoacetates introduced a spacer group which, after hydrolysis to the free acid, was acylated with amino acid esters or di- or tripeptide esters. The enzymatic assays proved some derivatives to be effective inhibitors of PPE and/or papain. N-BOC protected amino acid derivatives without a spacer group inhibited PPE reversibly, while derivatives with spacer group showed either weak or no inhibitory properties. On the other hand, papain was inactivated irreversibly by ethyl (RS)-2-oxo-4-phenylazetidin-1-acetate. The highest inhibitory activity against papain was found for the diastereomers of N-(2-oxo-4-phenylazetidin-1-acetyl)-L-alanyl-L-valine benzyl ester, a compound with a spacer group.
authors.affiliation: Lehrstuhl Pharmazeutische/Medizinische Chemie, Institut für Pharmazie, Ernst-Moritz-Arndt-Universität Greifswald, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Achilles
authors.forename: T
authors.initials: T
authors.lastname: Schirmeister
authors.forename: H H
authors.initials: HH
authors.lastname: Otto
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D001384:Azetidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D009842:Oligopeptides / Q000737:chemistry; D010196:Pancreatic Elastase / Q000037:antagonists & inhibitors; D010206:Papain / Q000037:antagonists & inhibitors; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship; D047090:beta-Lactams / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D000596:Amino Acids; D001384:Azetidines; D015853:Cysteine Proteinase Inhibitors; D009842:Oligopeptides; D011480:Protease Inhibitors; D015842:Serine Proteinase Inhibitors; D047090:beta-Lactams; D010196:Pancreatic Elastase; D010206:Papain