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Enhanced bioactivity of silybin B methylation products.
Bioorg Med Chem. 2013 Feb 01; 21(3):742-7.BM

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 h 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.

Authors+Show Affiliations

Department of Chemistry and Biochemistry, University of North Carolina at Greensboro, Greensboro, NC 27402, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

23260576

Citation

Sy-Cordero, Arlene A., et al. "Enhanced Bioactivity of Silybin B Methylation Products." Bioorganic & Medicinal Chemistry, vol. 21, no. 3, 2013, pp. 742-7.
Sy-Cordero AA, Graf TN, Runyon SP, et al. Enhanced bioactivity of silybin B methylation products. Bioorg Med Chem. 2013;21(3):742-7.
Sy-Cordero, A. A., Graf, T. N., Runyon, S. P., Wani, M. C., Kroll, D. J., Agarwal, R., Brantley, S. J., Paine, M. F., Polyak, S. J., & Oberlies, N. H. (2013). Enhanced bioactivity of silybin B methylation products. Bioorganic & Medicinal Chemistry, 21(3), 742-7. https://doi.org/10.1016/j.bmc.2012.11.035
Sy-Cordero AA, et al. Enhanced Bioactivity of Silybin B Methylation Products. Bioorg Med Chem. 2013 Feb 1;21(3):742-7. PubMed PMID: 23260576.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enhanced bioactivity of silybin B methylation products. AU - Sy-Cordero,Arlene A, AU - Graf,Tyler N, AU - Runyon,Scott P, AU - Wani,Mansukh C, AU - Kroll,David J, AU - Agarwal,Rajesh, AU - Brantley,Scott J, AU - Paine,Mary F, AU - Polyak,Stephen J, AU - Oberlies,Nicholas H, Y1 - 2012/12/05/ PY - 2012/09/04/received PY - 2012/11/14/revised PY - 2012/11/19/accepted PY - 2012/12/25/entrez PY - 2012/12/25/pubmed PY - 2013/11/5/medline SP - 742 EP - 7 JF - Bioorganic & medicinal chemistry JO - Bioorg. Med. Chem. VL - 21 IS - 3 N2 - 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 h 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. SN - 1464-3391 UR - https://www.unboundmedicine.com/medline/citation/23260576/Enhanced_bioactivity_of_silybin_B_methylation_products_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0968-0896(12)00928-5 DB - PRIME DP - Unbound Medicine ER -