Cyclic-disulfide-based prodrugs for cytosol-specific drug delivery.

The cytosolic conversion of therapeutically relevant nucleosides into bioactive triphosphates is often hampered by the inefficiency of the first kinase-mediated step. Nucleoside monophosphate prodrugs can be used to bypass this limitation. Herein we describe a novel cyclic-disulfide class of nucleoside monophosphate prodrugs with a cytosol-specific, reductive release trigger. The key event, a charge-dissipating reduction-triggered cyclodeesterification leads to robust cytosolic production of the cyclic 3',5'-monophosphate for downstream enzymatic processing. The antiviral competence of the platform was demonstrated with an O-benzyl-1,2-dithiane-4,5-diol ester of 2'-C-methyluridine-3',5'-phosphate. Both in vitro and in vivo comparison with the clinically efficacious ProTide prodrug of 2'-deoxy-2'-α-fluoro-β-C-methyluridine is provided. The cytosolic specificity of the release allows for a wide range of potential applications, from tissue-targeted drug delivery to intracellular imaging.