Milk thistle flavonolignans: biomimetic synthesis, synthesis of analogues and biological evaluation of synthetic products

UNCG Author/Contributor (non-UNCG co-authors, if there are any, appear on document)
Hanan Saad Althagafy (Creator)
The University of North Carolina at Greensboro (UNCG )
Web Site:
Nicholas Oberlies

Abstract: 7-O-methylflavonolignans from milk thistle were synthesized by first isolating the seven primary components of silymarin and individually methylating them. Optimization of conditions allowed for each of these seven compounds to be selectively methylated at the phenol in the 7-position in the presence of each metabolite's 4-5 other alcoholic positions without the use of protecting groups. These site-selectively methylated compounds were then evaluated for their cytotoxic and antiviral actions in the hepatoma cell line HuH7; in all cases the monomethylated analogues were more cytotoxic than the parent compounds. Moreover, parent compounds that were relatively non-toxic and inactive or weak inhibitors of hepatitis C virus infection had enhanced toxicity and anti-HCV activity upon 7-O-methylation. Also, the compounds were tested for inhibition of major drug metabolizing enzymes in pooled human liver and intestinal microsomes. Methylation of flavonolignans differentially modified inhibitory potency, with compounds demonstrating both increased and decreased potency depending upon the compound tested and the drug metabolizing enzyme system investigated. In total, these data indicated that monomethylation modulates the cytotoxic, antiviral, and drug interaction potential of silymarin flavonolignans. A biomimetic synthesis of flavonolignans was also accomplished. Coniferyl alcohol was oxidized using silver oxide in the presence of taxifolin to form four of the major components of silymarin, silibinin (silybin A and silybin B), and isosilibinin (isosilybin A and isosilybin B). The mechanism of this transformation was probed and it appears to undergo two sequential single electron oxidations with coupling of coniferyl alcohol to taxifolin between the two oxidations. Synthetic flavolignans were confirmed to be identical to natural compounds by NMR, HPLC, UPLC and HRMS. This results in a good yield of some of the minor natural compounds, such as isosilybin B. Moreover, it provides a means to generate structural analogues.

Additional Information

Language: English
Date: 2013
7-O-methylflavonolignans, Anti-Hepatitis C, Biomimetic, Flavonolignans, Milk Thistle, Synthesis
Milk thistle $x Cytochemistry
Milk thistle $x Analysis

Email this document to