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Abstract

Phosphoryloxymethyl carbonates and carbamates of the type R1R2X-CO-O-CH2-O-PO3(-2) (X = O or N) were evaluated as potentially novel water-soluble collapsible prodrugs for alcohols and amines. These were prepared by reaction of alpha-chloromethyl chloroformate with the starting alcohol or amine to give the corresponding alpha-chloromethyl carbonate or carbamate, respectively. Reaction with silver dibenzyl phosphate followed by debenzylation by hydrogenolysis gave the desired products. The aqueous chemical stability of the phosphoryloxymethylcarbonyl derivatives of 2-indanol (3a), beta-(3,4-dimethoxyphenyl)ethylamine (3b), and benzocaine (3c) were evaluated. The aqueous hydrolysis of 3a-3c resulted in regeneration of the parent alcohol or amines. As expected, the hydrolytic behaviors of these derivatives were found to differ from that of simple alkyl and aryl phosphomonoesters. The rates of hydrolysis were extremely rapid, with the dianionic phosphate species possessing a higher reactivity than the monoanionic species. This was attributed to the proximity of the phosphate group to the carbonyl moiety. The carbamate derivatives, 3b and 3c, displayed greater chemical stability compared to the carbonate derivative, 3a. Alkaline phosphatases-mediated hydrolysis of the phosphate ester bond in 3c led to a rapid cascade reaction resulting in regeneration of the parent amine, benzocaine. Although the alcohol derivative described here appeared to be too chemically unstable to be ideal as a prodrug, the derivatives of the amines might have some use. They are expected to be cleaved in vivo by alkaline phosphatases.

Energiedissipation aufgrund von Biegewellen bei Stoßvorgängen gegen dünne Platten

“…This led us to synthesize the mono‐Tris salt of our POMC prodrug, 19 d , which was highly water‐soluble (>20 mg mL −1 ), and decomposed relatively slowly in solution (88 % remained after one week at room temperature in D 2 O). The increased aqueous stability of the monoanionic prodrug relative to the dianionic prodrug is similar to that seen with Stella’s phosphoryloxymethyloxy carbonyl prodrugs and is consistent with his hypothesis that hydrolysis occurs primarily via an intramolecular general base or intramolecular nucleophilic catalysis mechanism 30. This hypothesis is further supported by data showing that adding an additional equivalent of Tris to 19 b has little effect on its stability in solution (Table 1, entry 19 e ).…”

“…However, no discussion of the properties of the potential prodrug was presented other than to mention that the material was not obtained cleanly. In addition, Stella and co‐workers explored related phosphoryloxymethyloxy carbonyl prodrugs of alcohols, aliphatic amines and aromatic amines, but found their potential utility limited by chemical instability 30…”

Covalent Immobilization of Unilamellar Liposomes in Gel Beads for Chromatography

“…We have thus proposed that the liposomes composed of phospholipids bind to the gel through a phosphodiester linkage between the phosphate moiety of the phospholipid and the carbonate moiety of the active group by nucleophilic phosphate catalysis (cf. 23,24). The hypothetical mechanism for the crosslinking of phospholipid vesicles in the gel matrix is illustrated in Fig.…”

Phosphonooxymethyl Prodrug of Triptolide: Synthesis, Physicochemical Characterization, and Efficacy in Human Colon Adenocarcinoma and Ovarian Cancer Xenografts

“…However, the lack of adequate chemical stability limited the commercial and clinical potential of this prodrug concept. 34 The chemical hydrolysis of 4 was followed at pH of 7.4 because the neutral pH range is perfectly suited for formulation delivery from a physiological perspective. We found that the hydrolysis of 4 followed pseudo-first-order kinetics.…”