alpha-Functionalized phosphonylphosphinates: synthesis and evaluation as transcarbamoylase inhibitors.
Diverse alpha-methyl-substituted phosphonylphosphinates (P-C-P-C-X) are accessible from a protected, pentafluorophenylsulfonated phosphonylphosphinate via nucleophilic displacement. The utility of this route is demonstrated with several nitrogen nucleophiles. The resulting amine and amino acid phosphonylphosphinate derivatives were evaluated as inhibitors of Streptococcus faecalis ornithine transcarbamoylase (OTC). Compared with the structurally related phosphonoacetyl-L-ornithine (L-PALO), a known inhibitor of OTCs from various sources, the phosphonylphosphinates are surprisingly poor inhibitors, binding several orders of magnitude less tightly to the enzyme. These results suggest that the tetrahedral intermediate formed in the normal transcarbamoylase reaction is poorly mimicked by a tetrahedral and anionic phosphonate, either because of directly unfavorable interactions with a hydrogen-bond acceptor within the active site or because transition-state analogues are unable to induce the protein conformation changes that normally accompany reaction.
Laboratorium für Organische Chemie, Swiss Federal Institute of Technology (ETH), Universitätstrasse 16, CH-8092 Zürich, Switzerland.
A
A
Flohr
A
A
Aemissegger
D
D
Hilvert
D003124:Colorimetry; D013293:Enterococcus faecalis / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D009954:Ornithine Carbamoyltransferase / Q000138:chemical synthesis* / Q000737:chemistry; D010721:Phosphinic Acids / Q000138:chemical synthesis* / Q000737:chemistry; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D010721:Phosphinic Acids; D009954:Ornithine Carbamoyltransferase