Synthesis of inhibitors of the meso-diaminopimelate-adding enzyme from Escherichia coli

In order to obtain inhibitors of the meso-diaminopimelate-adding enzyme, which participates in the biosynthesis of bacterial peptidoglycan, several Nα -propionyl-dipeptides of the general formula Pr-l-Ala-ambo-Xaa-OH were synthesized. Xaa represented methionine S,S-dioxide, methionine S-oxide, methionine sulfoximine, and 2-amino-4-phosphonobutyric acid, i.e. transition state analogs of glutamine synthetase and γ-glutamyl-cysteine synthetase, which catalyze the same type of reaction as our target enzyme. After synthesis, the diastereoisomers were separated by preparative HPLC or t.l.c.; those containing methionine derivatives could be identified thanks to previously synthesized reference compounds. After preincubation with the meso-diaminopimelate-adding activity from Escherichia coli. the ld diastereoisomers displayed moderate inhibitory effects, whereas the ll ones were inefficient. The best inhibition was obtained with one diastereoisomer of Pr-l-Ala-ζ-2-amino-4-phosphonobutyrate, presumably the ld one. A chloromethylketone derivative Pr-l-Ala-d-Glu(CH2Cl)-OH, potential affinity labeler of the meso-diaminopimelate-adding enzyme, was also synthesized. In the assay with preincubation, this compound behaved as the best inhibitor.