Minireview: nucleotide prodrugs

Nucleotides have shown interesting biological activities in a wide variety of antiviral, antiproliferative, immunomodulatory and other biological assays, and they present promising drug candidates. Because of their negative charge(s) nucleotides suffer from some disadvantages which can be successfully overcome by the utilization of nucleotide prodrugs. Nucleotide prodrugs were successfully used to increase oral absorption of nucleotides in vivo. By taking advantage of intracellular triggers (reducing potential, enzyme activity, pH), nucleotide prodrugs can be used in vitro for the intracellular delivery of the nucleotide resulting in enhanced potency and in some cases enhanced selectivity. Nucleotide prodrugs have also been utilized for tissue specific delivery of the nucleotides in vivo resulting in altered selectivity and reduced toxicity. For nucleotide prodrugs, their ultimate intended use is (in most cases) in vivo for the treatment of a disease. Thus, it is important to incorporate adequate assays and design criteria into any prodrug effort. In vivo systems are complicated because of metabolism, excretion and tissue distribution of the prodrug and the parent. Thus, results of in vitro assays have to be interpreted cautiously because they may be unsuitable predictors of the in vivo situation.