Abstract
For many decades, the design of new nucleoside analogs as potential therapeutic agents focused on both sugar and nucleobase modifications. These nucleoside analogs rely on cellular kinases to undergo stepwise addition of phosphate groups to form the corresponding active nucleoside triphosphate to express their therapeutic effect.1 However, nucleosides triphosphates cannot be considered as viable drug candidates as they usually have poor chemical stability along with high polarity that hinders them from transporting across cell membranes. Within the nucleoside analog phosphate activation process, the first phosphorylation has often been identified as the limiting step, which led medicinal chemists to prepare stable “protected” monophosphate nucleosides capable of delivering nucleoside monophosphates intracellularly. These nucleoside monophosphate prodrugs are designed to efficiently cross the biological barriers (as opposed to nucleoside monophosphates; Figure Figure1,1, eq 1) and reach the targeted cells or tissues. Once inside the cell, the biolabile protecting groups are then degraded enzymatically and/or chemically, releasing the free nucleoside analog in the monophosphate form, which can often efficiently express its therapeutical potency by intracellular conversion to the corresponding nucleoside triphosphate (Figure (Figure1,1, eq 2). Open in a separate window Figure 1 Mechanism of action of nucleoside monophosphate prodrugs.
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