Journal of Organic Chemistry 2013-09-20

Media effects on the mechanism of antioxidant action of silybin and 2,3-dehydrosilybin: role of the enol group.

Ewelina van Wenum, Rafal Jurczakowski, Grzegorz Litwinienko

Index: J. Org. Chem. 78(18) , 9102-12, (2013)

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Abstract

Silybin (SIL) and 2,3-dehydrosilybin (DHS) are constituents of milk thistle extract (silymarin) applied in the treatment of cirrhosis, hepatitis, and alcohol-induced liver disease. The molecular mechanism of their action is usually connected with antioxidant action. However, despite experimental and theoretical evidence for the antioxidant activity of SIL and DHS, the mechanism of their antiradical action still remains unclear. We studied the kinetics of SIL/DHS reactions with 2,2-diphenyl-1-picrylhydrazyl radical in organic solutions of different polarity and with peroxyl radicals in a micellar system mimicking the amphiphilic environment of lipid membranes. Kinetic studies together with determination of acidity and electrochemical measurements allowed us to discuss the structure-activity relationship in detail. In nonpolar solvents the reaction with free radicals proceeds via a one-step hydrogen atom transfer (HAT) mechanism, while significant acceleration of the reaction rates in methanol and water/methanol solutions suggests the dominating contribution of a sequential proton-loss electron-transfer (SPLET) mechanism with participation of the most acidic hydroxyl groups: 7-OH in SIL and 7-OH and 3-OH in DHS. In a heterogeneous water/lipid system, both mechanisms operate; however, the reaction kinetics and the antioxidant efficacy depend on the partition between lipid and water phases.