Improved delivery through biological membranes IX: Kinetics and mechanism of hydrolysis of methylsulfinymethyl 2-acetoxybenzoate and related aspirin prodrugs.

The complex kinetics and mechanism of the hydrolysis of the methylthiomethyl, methylsulfinylmethyl, and methylsulfonylmethyl 2-acetoxybenzoates, novel aspirin prodrugs, were studied. The pH profiles for the related salicylates and benzoates also were determined. Based on the activation parameters, isotope effects, and other data, it was established that the methylthiomethyl esters hydrolyze via a unimolecular alkyl-oxygen cleavage. The methylsulfinylmethyl and methylsulfonylmethyl 2-acetoxybenzoates undergo neutral hydrolysis of esters at pH greater than 4 to form aspirin, while water acts as a general base; but at lower pH, a different mechanism takes place and the o-acetyl group cleaves first, releasing the corresponding salicylates.