Synthesis and in vitro evaluation of aspartate transcarbamoylase inhibitors.
The design, synthesis, and evaluation of a series of novel inhibitors of aspartate transcarbamoylase (ATCase) are reported. Several submicromolar phosphorus-containing inhibitors are described, but all-carboxylate compounds are inactive. Compounds were synthesized to probe the postulated cyclic transition-state of the enzyme-catalyzed reaction. In addition, the associated role of the protonation state at the phosphorus acid moiety was evaluated using phosphinic and carboxylic acids. Although none of the synthesized inhibitors is more potent than N-phosphonacetyl-l-aspartate (PALA), the compounds provide useful mechanistic information, as well as the basis for the design of future inhibitors and/or prodrugs.
Coudray
Laëtitia
L
Department of Chemistry, Texas Christian University, Box 298860, Fort Worth, TX 76129, USA.
Pennebaker
Anne F
AF
Montchamp
Jean-Luc
JL
D001221:Aspartate Carbamoyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D001665:Binding Sites / Q000187:drug effects; D055162:Biocatalysis / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D004795:Enzyme Stability / Q000187:drug effects; D004926:Escherichia coli / Q000201:enzymology; D008956:Models, Chemical; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives / Q000737:chemistry; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D001224:Aspartic Acid; D001221:Aspartate Carbamoyltransferase; D010746:Phosphonoacetic Acid