1-Alkoxycarbonyl-3-bromoazetidin-2-ones as Potential Elastase Inhibitors

• Published in: European journal of organic chemistry Vol. 1999; no. 6; pp. 1441 - 1447
• Main Authors: Beauve, Cécile, Tjoens, Grégory, Touillaux, Roland, Lamotte-Brasseur, Josette, Marchand-Brynaert, Jacqueline, Fastrez, Jacques
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag GmbH 01.06.1999; WILEY‐VCH Verlag GmbH; Wiley
• Subjects: Azetidinones; Chemistry; Chemistry, Organic; Enzyme inhibitors; Kinetics; Molecular modelling; Physical Sciences; Science & Technology; ACID; MECHANISM; molecular modelling; BETA-LACTAM INHIBITORS; RESOLUTION; HUMAN-LEUKOCYTE ELASTASE; STEREOSPECIFIC SYNTHESIS; NEUTROPHIL ELASTASE; TRYPSIN-LIKE PROTEINASES; E-I-COMPLEXES; azetidinones; SUICIDE SUBSTRATE; enzyme inhibitors; kinetics
• ISSN: 1434-193X; 1099-0690
• DOI: 10.1002/(SICI)1099-0690(199906)1999:6<1441::AID-EJOC1441>3.0.CO;2-K

Three 1‐alkoxycarbonyl‐3‐bromoazetidin‐2‐ones have been prepared by reaction of (3S)‐3‐(tert‐butoxycarbonyl)aminoazetidin‐2‐one with benzyl, trichloroethyl, and trifluoroethyl chloroformates followed by tBoc deprotection, diazotation of the exocyclic amino function and its substitution with potassium bromide. The 3‐bromoazetidin‐2‐ones were obtained as racemic mixtures. Their hydroxide‐catalyzed hydrolysis exclusively affords ring‐opening products. Porcine pancreatic elastase (PPE) catalyzes the same reaction stereospecifically. Model building suggests that it is the (R) isomer that is enzymatically hydrolysed. The PPE‐catalyzed hydrolysis is characterised by low kcat and Km values. Accordingly, these compounds behave as transient inhibitors of the enzyme.