Hydrolysis and Solvent-Dependent 2′→5′ and 3′→5′ Acyl Migration in Prodrugs of 9-β-d-Arabinofuranosyladenine

• Published in: Journal of pharmaceutical sciences 1985-08, Vol.74 (8), p.825-830
• Main Authors: Anderson, Bradley D., Fung, Man-Cheong, Kumar, Shiv D., Baker, David C.
• Format: Article
• Language: English
• Subjects: Biological and medical sciences; General pharmacology; Medical sciences; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships
• ISSN: 0022-3549; 1520-6017
• 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.