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β‐Lactam Derivatives as Enzyme Inhibitors: 1‐Peptidyl Derivatives of 4‐Phenylazetidin‐2‐one as Inhibitors of Elastase and Papain
Author(s) -
Achilles Karin,
Schirmeister Tanja,
Otto HansHartwig
Publication year - 2000
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/1521-4184(20008)333:8<243::aid-ardp243>3.0.co;2-o
Subject(s) - chemistry , papain , enantiomer , tripeptide , stereochemistry , enzyme , enzyme inhibitor , serine proteinase inhibitors , diastereomer , chymotrypsin , amino acid , protease , serine protease , organic chemistry , biochemistry , trypsin
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 )‐β‐phenyl‐β‐alanine, while the ( R )‐enantiomer was obtained by enzymatic resolution with α‐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.