Inhibition of Carboxypeptidase A with$\beta$-Lactone-bearing phenylalanine. Design, Synthesis, and Stereochemistry-dependent Inhibition Mode

Inhibition of Carboxypeptidase A with$\beta$-Lactone-bearing phenylalanine. Design, Synthesis, and Stereochemistry-dependent Inhibition Mode

(3S,1'S)-3-(1'-Carboxy-2'-phenyl)ethylamino-2-oxetanone (1a) and (3R,1'S)-3-(1'-carboxy-2'-phenyl)ethylamino-2-oxetanone (1b) were designed, synthesized, and evaluated as inhibitors for carboxypeptidase A, a prototypical zinc protease that removes the C-terminal amino acid having an aromatic side chain from oligopeptide substrate. It was concluded from the analysis of inhibition kinetics that while 1a inactivates CPA irreversibly, its diastereoisomer, 1b is a weak competitive inhibitor for CPA. A possible explanation for the observed difference in inhibition mode that is dependent on the inhibitor stereochemistry is offered.