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J Med Chem. 1987 Nov;30(11):2062-7.

Design and synthesis of phosphonate inhibitors of glutamine synthetase.

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1
Department of Chemistry, Pennsylvania State University, University Park 16802.

Abstract

Inhibitors 1-4 have been shown previously to undergo enzymatic phosphorylation by glutamine synthetase (GS). Phosphonates 6-9 were designed as chemically stable analogues of these phosphorylated inhibitors, incorporating either a tetrahedral sulfur group (6-8) (-S-, -SO-, -SO2-) or phosphinate (9) adjacent to methylphosphonic acid. Phosphonates 6-8 resemble the transiently stable phosphorylated methionine sulfone (2), whereas 9 resembles phosphorylated 2-amino-4-phosphonobutyric acid (4). When tested as inhibitors of glutamine synthetase from bacteria, mammals, and plants, analogue 9 proved to be the most potent, with a Ki value of 7.5 X 10(-5) M vs. the Escherichia coli enzyme. Analysis of the inhibition data for 6-9 suggests that a replacement of the oxygen bridging the tetrahedral sulfur (6-8) or phosphinate (9) and the terminal phosphate with a hydrophobic methylene drastically reduces the enzyme's affinity for inhibitors. Enhanced affinity of GS for phosphonate 9 may result from interaction of the negative charge on the phosphinate with Mn2+ at the active site.

PMID:
2889829
DOI:
10.1021/jm00394a022
[Indexed for MEDLINE]

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