Investigation on the solid-phase synthesis of silybin prodrugs and their timed-release

Prodrugs are ingenious derivatives of therapeutic agents designed to improve the pharmacokinetic profile of thedrug. Here, we report an efficient and regioselective solid phase approach for obtaining new prodrugs of 9?? -silybins conjugated with 3? -ribonucleotide units (uridine and adenosine) as pro-moieties. Uridine and adenosineconjugates were obtained in good yields (41-50%), beginning with silibinin and its diastereomers (silybin A andsilybin B), using a NovaSyn® support functionalized with an ad hoc linker, which allowed selective detachmentof only the desired products. As expected, the solubility of both uridine and adenosine conjugates was higherthan that of the parental natural product (5 mg/mL and 3 mg/mL for uridine and adenosine, respectively). Ourinvestigations revealed that uridine conjugates were quickly cleaved by RNase A, releasing silybin drugs, even atlow enzyme concentrations. No toxic effects were found for any ribonucleotide conjugate on differentiatedneuroblastoma SH-SY5Y cells when tested at increasing concentrations. All results strongly encourage furtherinvestigations of uridine-silybin prodrugs as potential therapeutic agents for both oral and intravenous administration.The present synthetic approach represents a valuable strategy to the future design of new prodrugs withmodified nucleoside pro-moieties to modulate the pharmacokinetics of silybins or different natural products withstrong pharmacological activities but poor bioavailability.