Design and synthesis of γ-oxygenated phosphinothricins as inhibitors of glutamine synthetase

Abstract

The ability of L-γ-hydroxyglutamic acids to act as substrates of the enzyme glutamine synthetase (GS) was exploited as a rationale for the synthesis of γ-oxygenated analogues of the naturally occurring GS inhibitor phosphinothricin (PPT). The potent new inhibitor DL-γ-hydroxyphosphinothricin (GHPPT) was prepared via a key reaction involving the silicon-mediated addition of ethyl methylphosphinate to benzyl 2-benzyloxycarbonylamino-4-oxobutyrate. The resulting intermediate was also converted to various derivatives useful in probing structure–activity relationships in the GHPPT series. The γ-oxygenated phosphinothricins display enzyme inhibitory activity as well asin vivo phytotoxicity.