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Enhanced bioactivity of silybin B methylation products
- Source :
- Bioorganic & Medicinal Chemistry. 21:742-747
- Publication Year :
- 2013
- Publisher :
- Elsevier BV, 2013.
-
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 72 hr 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.
- Subjects :
- Stereochemistry
Clinical Biochemistry
Glucuronidation
Pharmaceutical Science
Silibinin
Hepacivirus
Microbial Sensitivity Tests
Antiviral Agents
Methylation
Biochemistry
Article
Silybum marianum
Flavonolignans
Structure-Activity Relationship
Dimethyl sulfate
chemistry.chemical_compound
In vivo
Drug Discovery
Humans
Structure–activity relationship
Enzyme Inhibitors
Molecular Biology
Cell Proliferation
Cytochrome P-450 CYP2C9
Dose-Response Relationship, Drug
Molecular Structure
biology
Organic Chemistry
biology.organism_classification
Antineoplastic Agents, Phytogenic
chemistry
Silybin
Microsomes, Liver
Microsome
Molecular Medicine
Aryl Hydrocarbon Hydroxylases
Drug Screening Assays, Antitumor
Silymarin
Subjects
Details
- ISSN :
- 09680896
- Volume :
- 21
- Database :
- OpenAIRE
- Journal :
- Bioorganic & Medicinal Chemistry
- Accession number :
- edsair.doi.dedup.....8235b16eafd95f27169f854f7052d846