New derivatives of silybin and 2,3-dehydrosilybin and their cytotoxic and P-glycoprotein modulatory activity

Large series of O-alkyl derivatives (methyl, benzyl) of silybin and 2,3-dehydrosilybin was prepared. Selective alkylation of the silybin molecule was systematically investigated. For the first time we present here, e.g. preparation of 19-nor-2,3-dehydrosilybin. All silybin derivatives were tested for cytotoxicity on panel of drugs sensitive against multidrug resistant cell lines and the ability to inhibit P-glycoprotein mediated efflux activity. We have identified four major groups of compounds. The first group contains the majority of 2,3-dehydrosilybin derivatives and is characterized both by significant in vitro anti-cancer activity and the capacity to block Pgp function. The second class of derivatives – both silybin and 2,3dehydrosilybin derivatives exhibited high cytotoxicity but no Pgp inhibition. Low or absent cytotoxicity but effective inhibition of Pgp was characteristic for third group of compounds represented by potential chemosensitizers (3,7,20-tri-O-methyl-2,3 dehydrosilybin). Finally, no significant cytotoxic and Pgp inhibitory activities were found for silybin itself compared to its more active derivatives. The presence of double bond in the position C-2 and C-3 of B ring (2,3-dehydrosilybin and its derivatives) and the substitution of C-3 hydroxyl are important for the Pgpinhibitory activity. Another important requisite for this activity is the benzylation of C-7 hydroxyl.
This work was supported by the Grant Agency of the Czech Republic (No.11 303/02/1097) and the Czech Ministry of Education (Research concepts No. MSM12 6198959216 and AV0Z50200510).