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Synthesis and Evaluation of Optical 2‐Benzyl‐5‐bromo‐4‐oxopentanoic Acids as Transition‐state Analog Inhibitors against Carboxypeptidase A
Author(s) -
JIN JingYi,
WANG ShouFeng,
XUAN Wei,
SHENG JiWen,
WANG SiHong,
TIAN GuanRong
Publication year - 2008
Publication title -
chinese journal of chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.28
H-Index - 41
eISSN - 1614-7065
pISSN - 1001-604X
DOI - 10.1002/cjoc.200890013
Subject(s) - chemistry , ketone , diazo , stereochemistry , electrophile , enantiomer , catalysis , medicinal chemistry , organic chemistry
Both enantiomers of 2‐benzyl‐5‐bromo‐4‐oxopentanoic acid were prepared utilizing the diazo ketones as the key intermediates. The compounds were assayed for inhibitory activity against carboxypeptidase A (CPA, EC 3.4.17.1). The ( R )‐form is 260‐fold more potent than the corresponding ( S )‐form. The finding that ( R )‐form, which belongs to the L ‐series, is mostly responsible for the inhibitory activity accords with the substrate specificity of CPA. For comparison, both the optical forms of 2‐benzyl‐4‐oxopentanoic acid were also synthesized and evaluated as the inhibitors against CPA. These results reveal that the introduction of a bromo group at the α ‐position of ketones can significantly enhance the electrophilicity of the carbonyl group. Further molecular docking study suggested that the gem ‐diol form of the α ‐bromo ketone, which mimics the transition state in the CPA catalytic process, could chelate the zinc ion in the active site of CPA and thus result in the strong inhibition.