Glutamate synthetase inhibitor

The mammalian folypolyglutamate synthetase inhibitor 230 is prepared from 2-desamino-10-thiapteroic acid (229) via coupling with glutamate using DEPC.8S... 

Structure-activity relationship studies testing different substituents on N-10 of 5,8-dideazafolic acid (Table 3), including 2-butyne and methylcyano groups, have shown that the propargyl analog was the best thymidylate synthetase inhibitor. It was also found that the glutamic acid was essential for thymidylate synthetase inhibition. ... 

Herbicidal properties of this compound as a commercially synthesized ammonium salt (glufosinate or HOE 39866) were first reported in 1977 ill41. This herbicide is presently marketed as BASTA by Hoechst AG. Some phosphonic and phosphinic acid analogs of glutamic acid have been known since 1959 to be inhibitors of glutamine synthetase (GS) (115). but not until 1972 was phosphinothricin found to be a potent inhibitor of GS activity (113)(Figure... 

The former can be prepared by reductive alkylation of 2-acetamido-5-amino-4(3H)pyrimidone with dimethyl iV-(p-(A-(formylmethyl)formamido)ben-zoyl -L-glutamate, followed by reformylation, partial deblocking, and acid hydrolysis to (LXIII). Both (LXIII) and (LXIV) were reported to have inhibitory activity against S. faecalis equal to that of aminopterin. They both inhibited dihydrofolate reductase (source not named) at 4 x 10" m, for 50 per cent inhibition. Compound (LXIII) is a better inhibitor of thymidylate synthetase than (LXIV) (3 x 10 vj. 7 x I0 M for 50 per cent inhibition). 

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