SYNTHESIS AND INVESTIGATION OF N-4-SUBSTITUTED CYTARABINE DERIVATIVESAS PRODRUGS

Esters of Cytarabine-N-4-carboxylates 2a-i and succinamates 3a-f were synthesized as prodrugs of cytarabine (Ara-C) with the aim of developi ng improved derivatives for oral or parentral administration. At pH 2 series 2 showed relative higher stability than 3, while both series of esters revealed matched stability at pH 7. All esters were susceptibl e to enzymatic hydrolysis by rat plasma and liver homogenate with half lives ranged from 0.14 h to 12 d, and showed improved stability again st cytidine deaminase. A parabolic relation was shown between K-obs of enzymatic hydrolysis and Vw. All compounds are more lipophilic than t he parent drug, Ara-C.