Hydrolysis and solvent-dependent 2'→5' and 3'→5' acyl migration in prodrugs of 9-β-D-arabinofuranosyladenine

Article abstract of DOI:10.1002/jps.2600740805

As a prerequisite to quantitative in vivo studies to further explore the promising topical activity of the 2',3'-di-O-acetyl derivative of 9-β-D-arabinofuranosyladenine (ara-A) against herpes virus infections, the kinetics of solution degradation of the 2',3'-di-O-acetyl derivative and the 2'-, 3'-, and 5'-monoacetates were investigated. The rates of aqueous solution hydrolysis were found to be consistent with rank order predictions based on a consideration of substituent effects. Preliminary in vivo hydrolysis data, however, do not correlate with such predictions, indicating a need for more systematic studies of the effect of molecular structure on enzyme-catalyzed hydrolysis. An important reaction of the 2',3'-diester and the 3'-monoester in aqueous solution, in addition to ester hydrolysis, is 3'→5' acyl migration. 2'→5' Acyl migration does not occur in water but is the predominant migration pathway in organic solvents, as verified by studies in acetonitrile. ¹H NMR spectroscopy was employed to study the dependence of the conformation of the sugar ring on the solvent environment. Although a change in the equilibrium between the C(2')endo and C(3')endo conformational states does occur, it is not a dramatic change and cannot explain the solvent selectivity observed in the acyl migration kinetics.