Stereoselective inhibition of glutamate carboxypeptidase by organophosphorus derivatives of glutamic acid
Stereoselective inhibition of glutamate carboxypeptidase by organophosphorus derivatives of glutamic acid
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DOI：
10.1016/j.bmc.2004.08.016
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发表时间：
2004-11-15
影响因子：
3.5
通讯作者：
Berkman, CE
中科院分区：
文献类型：
--
作者：
Mallari, JP;Choy, CJ;Berkman, CE
制备了一系列（S）-和（R）-谷氨酸的烷基和芳基膦酰基、硫代膦酰基和二硫代膦酰基衍生物，并检测了对谷氨酸羧肽酶（羧肽酶G）的抑制效力。通过共同的膦酰胺硫醇盐前体实现了膦酰胺二硫代酸和单独的膦酰胺硫代酸非对映异构体的获得，这也允许膦酰胺硫代酸的手性磷中心的色谱分离。该系列中最有效的抑制剂是谷氨酸天然异构体的正丁基磷酰胺衍生物。虽然每个非对映体对的三个膦酰胺硫代膦酸酯表现出立体选择性抑制与手性磷中心的配置一致，这种效果一般是不显着的。更重要的是，碳立体化学对谷氨酸羧肽酶抑制的影响，举例说明了一系列有限的对映体对的膦酰胺和膦酰胺基连二硫酸盐衍生物的谷氨酸。从谷氨酸的非天然立体异构体衍生的膦酰胺类似物与其对映异构体相比缺乏抑制效力。令人惊讶的是，衍生自谷氨酸的非天然立体异构体的膦酰氨基二硫代磺酸盐显示出比它们的天然衍生的对映体更大的抑制效力。(C)2004爱思唯尔有限公司保留所有权利。
A series of alkyl and aryl phosphonyl, thiophosphonyl, and dithiophosphonyl derivatives of (S)- and (R)-glutamic acid were prepared and examined for inhibitory potency against glutamate carboxypeptidase (carboxypeptidase G). The acquisition of the phosphonamidodithioic acids and the individual phosphonamidothioic acid diastereomers was achieved through a common phosphonamidothiolate precursor, which also allowed for the chromatographic resolution of the chiral phosphorus center of the phosphonamidothioic acids. The most potent inhibitor of the series was the n-butylphosphonamidate derivative of the natural isomer of glutamic acid. Although each diastereomeric pair of three phosphonamidothionates exhibited stereoselective inhibition consistent with the configuration of the chiral phosphorus center, this effect was generally not remarkable. More important, was the effect of carbon stereochemistry upon glutamate carboxypeptidase inhibition as exemplified by a limited series of enantiomeric pairs of phosphonamidate and phosphonamidodithionate derivatives of glutamic acid. The phosphonamidate analogs derived from the unnatural stereoisomer of glutamic acid were devoid of inhibitory potency in contrast to their enantiomers. Surprisingly, the phosphonamidodithionates derived from the unnatural stereoisomer of glutamic acid demonstrated greater inhibitory potency than their naturally-derived antipodes. (C) 2004 Elsevier Ltd. All rights reserved.