Steric parameters in PLE catalyzed hydrolysis of N⁴-substituted cytarabine ester prodrugs

The enzymatic hydrolysis of a series of Cytarabine-N4-carboxylate (3a-h) and succinamate (4a-f) ester prodrugs by porcine liver esterase (PLE) has been investigated. It was shown that variation of steric parameters such as van der Waal's volume of the ester side chain (V(XR')), molecular bulkiness (V(m)) and linear dimensions (L) can clearly influence the rate of conversion of the prodrugs to the parent Ara-C. Regression analysis of the results permitted the prediction of minimum (V(XR')) values of 51.5 Å3 and 85.0 Å3 for the carbamates and succinamates, respectively. In general, the carbamate esters 3a-h were more resistant to hydrolysis by PLE than the succinamates 4a-f. The rate of hydrolysis increased as the molecular bulkiness (V(m)) increased, but this effect can be compensated in some cases by the inverse correlation of the linear dimension (L) as in case of the cholesteryl ester prodrug. The study indicates that, through a suitable choice of an ester group with balanced V(m) and L parameters, one can tune up the enzymatic hydrolysis of Ara-C prodrugs by PLE.