Stereoselective inhibition of glutamate carboxypeptidase by organophosphorus derivatives of glutamic acid.
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.
Mallari
Jeremy P
JP
Department of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway Ave., San Francisco, CA 94132, USA.
Choy
Cindy J
CJ
Hu
Ying
Y
Martinez
Alicia R
AR
Hosaka
Mia
M
Toriyabe
Yoko
Y
Maung
Jack
J
Blecha
Joseph E
JE
Pavkovic
Stephen F
SF
Berkman
Clifford E
CE
D002268:Carboxypeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018698:Glutamic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D009943:Organophosphorus Compounds / Q000737:chemistry* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism
D009943:Organophosphorus Compounds; D011480:Protease Inhibitors; D018698:Glutamic Acid; D002268:Carboxypeptidases; C026134:glutamate carboxypeptidase