Design, synthesis, and bioactivity of novel inhibitors of E. coli aspartate transcarbamoylase.
A series of inhibitors of the aspartate transcarbamoylase, an enzyme involved in pyrimidine nucleotide biosynthesis, has been synthesized. These inhibitors are analogues of a highly potent inhibitor of this enzyme, N-phosphonacetyl-L-aspartate (PALA). Analogues have been synthesized with modifications at the alpha- and beta-carboxylates as well as at the aspartate moiety. The ability of these compounds to inhibit the enzyme was evaluated. These studies, with functional group modified PALA derivatives, showed that amide groups can be a useful substitute of the carboxylate in order to reduce the charge on the molecule, and indicate that the relative position of the functional group in the beta-position is more critical than the nature of the functional group. Some of the molecules synthesized here are potent inhibitors of the enzyme.
Eldo
Joby
J
Boston College, Department of Chemistry, Merkert Chemistry Center, Chestnut Hill, MA 02467, USA.
Heng
Sabrina
S
Kantrowitz
Evan R
ER
D000577:Amides / Q000737:chemistry; D001221:Aspartate Carbamoyltransferase / Q000037:antagonists & inhibitors*; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D020134:Catalytic Domain; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D015195:Drug Design; D004926:Escherichia coli / Q000201:enzymology*; D007700:Kinetics; D008956:Models, Chemical; D008968:Molecular Conformation; D015394:Molecular Structure; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D000577:Amides; D001224:Aspartic Acid; C013195:sparfosic acid; D001221:Aspartate Carbamoyltransferase; D010746:Phosphonoacetic Acid