Hydrolysis of pharmaceutically relevant phosphate monoester monoanions: correlation to an established structure-reactivity relationship.

The kinetics of dephosphorylation of dilute aqueous solutions of 3-phosphoryloxymethyl-5,5-diphenylhydantoin (1) and estrone phosphate (2) were studied as a function of pH, buffer concentration, and temperature at an ionic strength of 0.5 M. The resulting pH-rate profiles displayed bell-shaped regions with maxima between pH 3 and 5, where the monoanionic phosphate species predominate; mechanistically, these regions involved spontaneous or water-catalyzed dephosphorylation of the monoanionic phosphate species. The profile of 1 was also described with pathways involving a hydronium ion-catalyzed and a spontaneous or water-catalyzed dephosphorylation of the neutral species. The hydrolytic reactivities of the monoanionic species of the phosphomonoester prodrugs of phenytoin (i.e., 1), estrone (i.e., 2), and 2,2,2-trichloroethanol (from the literature) were well predicted by an established structure-reactivity, free-energy relationship. The correlation of these compounds to this relationship supported a common hydrolytic reaction mechanism. The small Brønsted value of -0.27 was consistent with a dephosphorylation mechanism involving a rapid transfer of the lone phosphoryl proton to the bridge-oxygen atom of the ester linkage, followed by the rate-limiting phosphorus-oxygen bond fission proceeding through a largely dissociative transition state.