Effects of 5′-Ester Modification on the Physicochemical Properties and Plasma Protein Binding of 5-Iodo-2′-deoxyuridine

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Abstract
A series of 5′-(O-acyl and O-benzoyl) derivatives of 5-iodo-2′-deoxyuridine (IDU) was synthesized by direct acylation of the parent nucleoside in a pyridine-N,N′-dimethylformamide mixture (1:1). Aqueous solubilities in phosphate buffer (pH 7.4), partition coefficients in 1-octanol/phosphate buffer (pH 7.4), plasma protein binding properties, and plasma reversion kinetics of these potential prodrugs were evaluated. The esters showed an expected increase in lipophilicity with a corresponding decrease in aqueous solubility relative to the parent compound. The association constants (Ka) with albumin also exhibited a good linear correlation with the lipophilicity of the compounds. However, the reversion rate constants in plasma varied with the steric and polar nature of the acyl or benzoyl substituent.