Journal article
Stereoselective inhibition of glutamate carboxypeptidase by organophosphorus derivatives of glutamic acid
Bioorganic & medicinal chemistry, Vol.12(22), pp.6011-6020
2004
Handle:
https://hdl.handle.net/2376/108013
PMID: 15498677
Abstract
A series of phosphonyl, thiophosphonyl, and dithiophosphonyl derivatives of glutamic acid were prepared and examined for inhibitory potency against glutamate carboxypeptidase (carboxypeptidase G). Although varied in extent, stereoselective inhibition was dependent upon both carbon and phosphorus stereochemistry.
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.
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Details
- Title
- Stereoselective inhibition of glutamate carboxypeptidase by organophosphorus derivatives of glutamic acid
- Creators
- Jeremy P Mallari - Department of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway Ave., San Francisco, CA 94132, USACindy J Choy - Department of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway Ave., San Francisco, CA 94132, USAYing Hu - Department of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway Ave., San Francisco, CA 94132, USAAlicia R Martinez - Department of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway Ave., San Francisco, CA 94132, USAMia Hosaka - Department of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway Ave., San Francisco, CA 94132, USAYoko Toriyabe - Department of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway Ave., San Francisco, CA 94132, USAJack Maung - Department of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway Ave., San Francisco, CA 94132, USAJoseph E Blecha - Department of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway Ave., San Francisco, CA 94132, USAStephen F Pavkovic - Department of Chemistry, Loyola University of Chicago, 6525 N. Sheridan Rd, Chicago, IL 60626, USAClifford E Berkman - Department of Chemistry and Biochemistry, San Francisco State University, 1600 Holloway Ave., San Francisco, CA 94132, USA
- Publication Details
- Bioorganic & medicinal chemistry, Vol.12(22), pp.6011-6020
- Academic Unit
- Chemistry, Department of
- Publisher
- Elsevier Ltd
- Identifiers
- 99900547750601842
- Language
- English
- Resource Type
- Journal article