Molecules 2007-01-01

Bioreversible derivatives of phenol. 2. Reactivity of carbonate esters with fatty acid-like structures towards hydrolysis in aqueous solutions.

Jesper Østergaard, Claus Larsen

Index: Molecules 12(10) , 2396-412, (2007)

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Abstract

A series of model phenol carbonate ester prodrugs encompassing derivatives with fatty acid-like structures were synthesized and their stability as a function of pH (range 0.4 - 12.5) at 37 degrees C in aqueous buffer solutions investigated. The hydrolysis rates in aqueous solutions differed widely, depending on the selected pro-moieties (alkyl and aryl substituents). The observed reactivity differences could be rationalized by the inductive and steric properties of the substituent groups when taking into account that the mechanism of hydrolysis may change when the type of pro-moiety is altered, e.g. n-alkyl vs. t-butyl. Hydrolysis of the phenolic carbonate ester 2-(phenoxycarbonyloxy)-acetic acid was increased due to intramolecular catalysis, as compared to the derivatives synthesized from omega-hydroxy carboxylic acids with longer alkyl chains. The carbonate esters appear to be less reactive towards specific acid and base catalyzed hydrolysis than phenyl acetate. The results underline that it is unrealistic to expect that phenolic carbonate ester prodrugs can be utilized in ready to use aqueous formulations. The stability of the carbonate ester derivatives with fatty acid-like structures, expected to interact with the plasma protein human serum albumin, proved sufficient for further in vitro and in vivo evaluation of the potential of utilizing HSA binding in combination with the prodrug approach for optimization of drug pharmacokinetics.