Chemo-Enzymatic Synthesis of Silybin and 2,3-Dehydrosilybin Dimers

Abstract

Divalent or multivalent molecules often show enhanced biological activity relative to the simple monomeric units. Here we present enzymatically and chemically prepared dimers of the flavonolignans silybin and 2,3-dehydrosilybin. Their electrochemical behavior was studied by in situ and ex situ square wave voltammetry. The oxidation of monomers and dimers was similar, but adsorption onto the electrode and cell surfaces was different. A 1,1-diphenyl-2-picrylhydrazyl (DPPH) and an inhibition of microsomal lipoperoxidation assay were performed with same trend of results for silybin and 2,3-dehydrosilybin dimers. Silybin dimer showed better activity than the monomer, while on the contrary 2,3-dehydrosilybin dimer presented weaker antioxidant/antilipoperoxidant activity than its monomer. Cytotoxicity was evaluated on human umbilical vein endothelial cells, normal human adult keratinocytes, mouse fibroblasts (BALB/c 3T3) and human liver hepatocellular carcinoma cell line (HepG2). Silybin dimer was more cytotoxic than the parent compound and in the case of 2,3-dehydrosilybin its dimer showed weaker cytotoxicity than the monomer.

Chemoenzymatic Preparation and Biophysical Properties of Sulfated Quercetin Metabolites

“…Reducing capacity was evaluated using Folin–Ciocalteau reagent [ 26 ] with minor modifications as described previously [ 27 , 28 , 29 ]. Antiradical activity was evaluated spectrophotometrically as the ability of the substances to reduce the DPPH radical as described previously [ 30 ] with minor modifications [ 27 , 28 , 29 ]. DMPD [ 31 ] radical scavenging and FRAP [ 32 ] were measured using kits from Bioquochem (Llanera–Asturias, Spain).…”

“…Inhibition of microsomal lipid peroxidation was tested using pooled microsomes from male rat livers oxidatively damaged by tert -butylhydroperoxide in PBS. Determination of lipid peroxidation products as thiobarbituric acid reactive substances (TBARS) and calculation of the IC 50 values were performed as previously described [ 27 , 28 , 29 ].…”

Dicarboxylic esters: Useful tools for the biocatalyzed synthesis of hybrid compounds and polymers

“…Similarly, dimers of sylibin ( 11a , b , Fig. 3 ) and dehydrosylibin, obtained by Novozyme 435-catalyzed acylation with the divinyl esters of dodecanedioc acid, were evaluated in terms of antioxidant activity and cytotoxicity [ 29 ].…”

“…The obvious hypothesis related to the synthesis of these compounds was that a dimer should be more bioactive than a monomer, but this was not always the case [ 28 – 29 ].…”

Regioselective Alcoholysis of Silychristin Acetates Catalyzed by Lipases

“…Enzymatic protection/deprotection of primary OH groups has been reported to be useful in multi-step organic synthesis of flavonolignans. Acyl formations by lipases were used for the preparation of several derivatives of silymarin compounds, e.g., silybin [ 11 ]. For instance, acetylation at C-23 OH of silybin diastereomeric mixture and the following selective hydrolysis afforded optically pure diastereoisomers in multi-gram quantities [ 12 , 13 , 14 ].…”