Phosphonate prodrugs: an overview and recent advances

Phosphonates, often used as isosteric replacements for phosphates, can provide important interactions with an enzyme. Due to their high charge at physiological pH, however, permeation into cells can be a challenge. Protecting phosphonates as prodrugs has shown promise in drug delivery. Thus, a variety of structures and cleavage/activation mechanisms exist, enabling release of the active compound. This review describes the structural diversity of these pro-moieties, relevant cleavage mechanisms and recent advances in the design of phosphonate prodrugs.