Cysteine derivatives as inhibitors for carboxypeptidase A: synthesis and structure-activity relationships.
A series of cysteine (Cys) derivatives having an alkyl or arylalkyl moiety on the alpha-amino group of the amino acid have been synthesized as a novel type of inhibitor for carboxypeptidase A. These compounds are readily prepared starting with Cys in an optically active form. The structure-activity relationship study revealed that the inhibitors prepared from D-Cys are much more potent than the corresponding inhibitors obtained from L-Cys, and the most potent inhibitor in the series, (S)-1j with a K(i) value of 55 +/- 4 nM, is obtained by introducing a phenethyl moiety on the amino group of D-Cys. In comparison, the most active inhibitor in the series of 2-substituted 3-mercaptopropanoic acid is found to be 20, in which the phenyl ring is linked to the mercaptocarboxylic acid at the alpha-position with a methylene unit. A proposal that accounts for the different structural requirement for the maximum activity between the two series of inhibitors is provided.
Park
Jung Dae
JD
Department of Chemistry, Division of Molecular and Life Science, Pohang University of Science and Technology, San 31, Hyojadong, Namku, Pohang 790-784, Korea.
Kim
Dong H
DH
D002268:Carboxypeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D043422:Carboxypeptidases A; D003545:Cysteine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D010666:Phenylpropionates / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
C448631:2-(mercaptomethyl)-3-phenylpropanoic acid; D004791:Enzyme Inhibitors; C448630:N-phenethylcysteine; D010666:Phenylpropionates; D002268:Carboxypeptidases; D043422:Carboxypeptidases A; D003545:Cysteine