Synthesis and Evaluation of Optical 2-Benzyl-5-bromo-4- oxopentanoic Acids as Transition-state Analog Inhibitors against Carboxypeptidase A

• 来源期刊: 中国化学（英文版）
• 年，卷（期）: 2008,（1）
• 页码范围: 153-157
• 页数: 5页
• 语种: 英文

摘要

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.