alpha-Functionalized phosphonylphosphinates: Synthesis and evaluation as transcarbamoylase inhibitors

Diverse alpha-methyl-substituted phosphonylphosphinates (P-C-P-C-X) are acc essible from a protected, pentafluorophenylsulfonated phosphonylphosphinate via nucleophilic displacement. The utility of this route is demonstrated w ith several nitrogen nucleophiles. The resulting amine and amino acid phosp honylphosphinate 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 fro m various sources, the phosphonylphosphinates are surprisingly poor inhibit ors, binding several orders of magnitude less tightly to the enzyme. These results suggest that the tetrahedral intermediate formed in the normal tran scarbamoylase reaction is poorly mimicked by a tetrahedral and anionic phos phonate, either because of directly unfavorable interactions with a hydroge n-bond acceptor within the active site or because transition-state analogue s are unable to induce the protein conformation changes that normally accom pany reaction.