Enol esters as potential pro-drugs II. In vitro aqueous stability and enzyme-mediated hydrolysis of several enol esters of acetophenone

Several α-acyloxystyrenes were synthesized and evaluated as models of enol esters which might be used in pro-drug design. Their stabilities were evaluated in aqueous buffered solutions at various pH values and temperatures, and in human and rat plasma and tissue homogenates at 37°C. The enol esters studied were relatively stable in neutral aqueous media, but most hydrolyzed rapidly and completely to yield the parent ketone (acetophenone) with the aid of enzymatic catalysis in the biological media used. The aqueous and enzymatic rates of hydrolysis were substantially affected by the nature of the acyl group. The results of this study indicate that enol esters are rather stable yet bioreversible derivatives of ketones and therefore may be useful as pro-drugs of agents containing enolizable carboxyl groups.