alpha-Functionalized phosphonylphosphinates: synthesis and evaluation as transcarbamoylase inhibitors.

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Flohr A, Aemissegger A, Hilvert D

alpha-Functionalized phosphonylphosphinates: synthesis and evaluation as transcarbamoylase inhibitors.

J Med Chem. 1999 Jul 15;42(14):2633-40.

PubMed ID

10411483 [ View in PubMed

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Abstract

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
N-(Phosphonoacetyl)-L-Ornithine	Ornithine carbamoyltransferase, mitochondrial	Ki (nM)	130	N/A	N/A	Details
N-(Phosphonoacetyl)-L-Ornithine	Ornithine carbamoyltransferase, mitochondrial	Ki (nM)	200	N/A	N/A	Details
N-(Phosphonoacetyl)-L-Ornithine	Ornithine carbamoyltransferase, mitochondrial	Ki (nM)	100	N/A	N/A	Details