Silibinin phosphate-based flavonolignans: new emerging synthetic metabolites with interesting pharmacological properties

Many drug candidates have been reported to possess a strong therapeutic potential in vitro but they have failed in vivo because of their poor pharmacokinetic behaviour, very often due to the low water solubility. There are many formulations and drug design strategies that can be used to overcome solubility issues. The design and synthesis of soluble pro-drugs is one of the most common approach used. In this frame, the phosphate group is a useful tool for the enhancement of aqueous solubility of phenolic and other metabolites, in addition it displayed excellent chemical stability and rapid bioconversion in vivo to the parent drug by phosphatases. On the other hand, also the conjugation of specific molecules recognized by a receptor on the target cell could be a successful strategy. In our studies, we have combined both aspects through the synthesis of new phosphodiester modified Silibinin with a good water solubility, as well as, attractive antioxidant properties. In the past decade, Silibinin has received more attention due to its large variety of activities ranging from anticancer and chemopreventive actions to hypocholesterolemic, cardioprotective and neuroprotective activities. Unfortunately, the bioavailability and the therapeutic efficiency of Silibinin are rather limited by its low water-solubility. In this work, we present the synthesis of a new library of modified Silibinins and related studies of their redox behaviour. Exploiting the selective protection of the hydroxyl groups of the Silibinin, we developed an efficient strategy for the synthesis of Silibinin phosphate-based flavonolignans consisting of phosphodiester glycoconjugates and dimers of Silibinin. The water solubility, the radical scavenger efficiency and the ability to scavenge different reactive oxygen species (ROS) have been evaluated for the new phosphodiester modified Silibinins in comparison to Silibinin. Moreover, the serum stability, and their cytoprotective (X/XO assay on HepG2 cells) behaviours have been studied. The remarkable antioxidant activity and the high water solubility (compared to Silibinin) make Silibinin phosphatebased flavonolignans promising molecules for future studies.