Journal article
Enhanced bioactivity of silybin B methylation products
Bioorganic & medicinal chemistry, Vol.21(3), pp.742-747
02/01/2013
Handle:
https://hdl.handle.net/2376/110453
PMCID: PMC3630461
PMID: 23260576
Abstract
Flavonolignans from milk thistle (Silybum marianum) have been investigated for their cellular modulatory properties, including cancer chemoprevention and hepatoprotection, as an extract (silymarin), as partially purified mixtures (silibinin and isosilibinin), and as pure compounds (a series of seven isomers). One challenge with the use of these compounds in vivo is their relatively short half-life due to conjugation, particularly glucuronidation. In an attempt to generate analogues with improved in vivo properties, particularly reduced metabolic liability, a semi-synthetic series was prepared in which the hydroxy groups of silybin B were alkylated. A total of five methylated analogues of silybin B were synthesized using standard alkylation conditions (dimethyl sulfate and potassium carbonate in acetone), purified using preparative HPLC, and elucidated via spectroscopy and spectrometry. Of the five, one was monomethylated (3), one was dimethylated (4), two were trimethylated (2 and 6), and one was tetramethylated (5). The relative potency of all compounds was determined in a 72h growth-inhibition assay against a panel of three prostate cancer cell lines (DU-145, PC-3, and LNCaP) and a human hepatoma cell line (Huh7.5.1) and compared to natural silybin B. Compounds also were evaluated for inhibition of both cytochrome P450 2C9 (CYP2C9) activity in human liver microsomes and hepatitis C virus infection in Huh7.5.1 cells. The monomethyl and dimethyl analogues were shown to have enhanced activity in terms of cytotoxicity, CYP2C9 inhibitory potency, and antiviral activity (up to 6-fold increased potency) compared to the parent compound, silybin B. In total, these data suggested that methylation of flavonolignans can increase bioactivity.
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Details
- Title
- Enhanced bioactivity of silybin B methylation products
- Creators
- Arlene A Sy-Cordero - Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC 27402, USATyler N Graf - Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC 27402, USAScott P Runyon - Center for Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, NC 27709, USAMansukh C Wani - Natural Products Laboratory, Research Triangle Institute, Research Triangle Park, NC 27709, USADavid J Kroll - Department of Pharmaceutical Sciences, BRITE, North Carolina Central University, Durham, NC 27707, USARajesh Agarwal - Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Denver, Aurora, CO 80045, USAScott J Brantley - Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USAMary F Paine - Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USAStephen J Polyak - Department of Laboratory Medicine, University of Washington, Seattle, WA 98104, USANicholas H Oberlies - Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC 27402, USA
- Publication Details
- Bioorganic & medicinal chemistry, Vol.21(3), pp.742-747
- Academic Unit
- Pharmaceutical Sciences, Department of
- Publisher
- Elsevier Ltd
- Identifiers
- 99900547106501842
- Language
- English
- Resource Type
- Journal article