Synthesis, Redox and Biological Activities of New Silibinin Derivatives

Polyphenols are widely distributed in nature and and very often represent the active compounds of the medicinal plants from which they can be isolated. Many studies suggests that the mechanisms by which plant polyphenols exert their protective actions against cardiovascular and neurodegenerative diseases, as well as cancer and diabetes, are due to their redox properties and their ability to directly bind bio-targets (peptides, proteins, nucleic acids).[1] To this huge group of metabolites belongs Silibinin, [2] the major biologically active component of Silymarin extracted from the seeds of the milk thistle [Silybum marianum (L.) Gaertn.]. In the past decade Silibinin has received attention due to its anticancer and chemopreventive actions, [3] as well as hypocholesterolemic, [4] cardioprotective and neuroprotective [5] activities. Unfortunately, the bioavailability and therapeutic efficiency of Silibinin are rather limited by its low water-solubility, therefore new synthetic approaches for selectively modifying Silibinin are of high interest. Different approaches have been recently described in order to improve its bioavailability, including the synthesis of new derivatives, the complexation with β-cyclodextrins or phospholipids, liposomes and phytosomes. As part of our ongoing efforts towards the exploitation of a readily available natural product used as a scaffold for chemical diversification, we recently considered Silibinin as a versatile starting material. Exploiting the regioselective protection of its hydroxyl groups and the well-known phosphoramidite chemistry, we developed an efficient strategy for the synthesis of a variety of Silibinin and 2,3-dehydrosilybin modified, bearing different groups at position C-9" (amino, sulphate),[6] and also inserting a suitable conjugation by a phosphodiester bound.[7, 8] By combinatorial solution phase strategies, a large family of Silibinin derivatives was successfully realized in a short time and in very good yields. For the conjugation, we have selected some molecules known for their ability to act as molecular carriers (steroids, bile acids), and able to improve water solubility (polyether) and radical scavenging activity (nucleosides). The redox behaviour of new Silibinin derivatives were analysed by potentiometric and voltammetric studies; moreover the scavenging activity was evaluated both in vitro by radical scavenger test and on cells by X/XO assay.