Intramolecular Catalysis of the Hydrolysis of Polycarboxylic Acid Prodrugs
Innes, Jennifer B.
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With the goal of rapid regeneration independent of enzyme action in mind, this project will examine the kinetics and mechanisms of the hydrolysis of certain carboxylic acid esters. Ester linkages are common in prodrugs, and hydrolysis of the link releases the parent drug from the pro-moiety. Ester hydrolysis does not normally occur rapidly, particularly when there is a great deal of steric hindrance around the ester linkage, but the citrate ester of flurbiprofen, expected to be quite stable due to steric hirndrance by three carboxyl groups, has been found to hydrolyze readily at certain pH's. The proposed mechanism involves an intramolecular catalysis by the carboxyl groups of the citrate. While flurbiprofen citrate has not proven viable for drug use, its mechanism of hydrolysis is interesting in that it suggests that intramolecular catalysis may offer a way to control drug release by non-enzymatic means.