Rational development of a soluble prodrug of a cytotoxic nucleoside: preparation and properties of arabinosyladenine 5'-formate.
The 5'-O-formate ester of arabinosyladenine was synthesized and shown to be suitable as a water-soluble prodrug, being at least 60 times more soluble than the parent cytotoxic nucleoside. This increased solubility was ascribed to a decrease in intermolecular interaction in the crystalline state, as evidenced by an similar 90 degrees lower melting point for the ester relative to the parent compound. The prodrug reverted to the parent compound in aqueous solution, its pH-rate profile being V-shaped with maximum stability at a pH similar 4.2, corresponding to a half-life of about 10 days. The rate of hydrolysis of the prodrug at 37degrees in 91% human serum and 91% whole blood was studied. At an initial concentration of 0.4 mg of prodrug/ml of 91% whole blood, reversion to arabinosyladenine appeared to be essentially complete in about 15 min. The prodrug did not appear to be subject to enzymatic deamination. This feature, together with the good solubility of the prodrug, makes possible the effective formulation of arabinosyladenine for intravenous purposes. The rationale involved in the general design of a prodrug and the specific considerations necessitated in the case of adenine arabinoside are discussed.
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D005260:Female; D005561:Formates / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D066298:In Vitro Techniques; D007700:Kinetics; D051379:Mice; D011684:Purine Nucleosides; D014740:Vidarabine / Q000138:chemical synthesis / Q000494:pharmacology
D000970:Antineoplastic Agents; D005561:Formates; D011684:Purine Nucleosides; D014740:Vidarabine