Institute of Crystallography - CNR

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 the
drug. 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 adenosine
conjugates were obtained in good yields (41-50%), beginning with silibinin and its diastereomers (silybin A and
silybin B), using a NovaSyn® support functionalized with an ad hoc linker, which allowed selective detachment
of only the desired products. As expected, the solubility of both uridine and adenosine conjugates was higher
than that of the parental natural product (5 mg/mL and 3 mg/mL for uridine and adenosine, respectively). Our
investigations revealed that uridine conjugates were quickly cleaved by RNase A, releasing silybin drugs, even at
low enzyme concentrations. No toxic effects were found for any ribonucleotide conjugate on differentiated
neuroblastoma SH-SY5Y cells when tested at increasing concentrations. All results strongly encourage further
investigations 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 with
modified nucleoside pro-moieties to modulate the pharmacokinetics of silybins or different natural products with
strong pharmacological activities but poor bioavailability.

Bioorganic & medicinal chemistry (Online)
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Valeria Romanucci a, Maddalena Giordano a, Rita Pagano a, Stefania Zimbone b, Maria Laura Giuffrida b, Danilo Milardi b, Armando Zarrelli a, Giovanni Di Fabio a,*