Aqueous conversion kinetics and mechanisms of ancitabine, a prodrug of the antileukemic agent cytarabine

Article abstract of DOI:10.1002/jps.2600730709

The kinetics of conversion of the prodrug ancitabine to the anti-cancer drug cytarabine have been studied in aqueous solutions in the pH range of 1.5-10.7, temperature range of 19.5-80.0°C, ionic strength range of 10^-4 to 1.5, and in the presence of several general-base catalysts. Under all conditions ancitabine was quantitatively converted to cytarabine. The pH-rate profiles were linear with slope = 1 in alkaline pH, becoming pH independent in the region of maximum stability at pH ≤4, where buffer catalysis was found to be insignificant and k(obs) ? (1.12 x 10¹¹ h^-1)·exp {-10121 deg/T}. At 30°C, pH ≤4, it is calculated that an aqueous ancitabine solution will maintain 90% of its initial concentration for 12 d. A novel method for measuring general-base catalysis in competition with predominating a specific-base catalysis and in the presence of secondary salt effects a constant ionic strength was developed. Three mechanisms of hydrolytic prodrug conversion are proposed: nucleophilic hydroxide addition, general base-assisted nucleophilic water attack, and spontaneous water attack.