STERIC PARAMETERS IN PLE CATALYZED-HYDROLYSIS OF N-4-SUBSTITUTED CYTARABINE ESTER PRODRUGS

The enzymatic hydrolysis of a series of Cytarabine-N-4-carboxylate (3a -h) and succinamate (4a-f) ester prodrugs by porcine liver esterase (P LE) has been investigated. It was shown that variation of steric param eters such as van der Waal's volume of the ester side chain (V-XR'), m olecular bulkiness (V-m) and linear dimensions (L) can clearly influen ce the rate of conversion of the prodrugs to the parent Ara-C. Regress ion analysis of the results permitted the prediction of minimum (V-XR' ) values of 51.5 Angstrom(3) and 85.0 Angstrom(3) for the carbamates a nd succinamates, respectively. In general, the carbamate esters 3a-h w ere more resistant to hydrolysis by PLE than the succinamates 4a-f. Th e rate of hydrolysis increased as the molecular bulkiness (V-m) increa sed, but this effect can be compensated in some cases by the inverse c orrelation of the linear dimension (L) as in case of the cholesteryl e ster prodrug. The study indicates that, through a suitable choice of a n ester group with balanced V-m and L parameters, one can tune up the enzymatic hydrolysis of Ara-C prodrugs by PLE.