Issues‎ > ‎vol17n3‎ > ‎

Bioavailability Enhancement of Silybin Through Carbon-23 Acid Derivatization


Lena Nawzad Amin1, Mohammed N. Sabir2, Emad Manhal Al-Khafaji3 &  Shwan Rachid4

1,2 School of Pharmacy, Dept. of Pharmacognosy & Pharmaceutical Chemistry, Sulaimani University
3 Faculty of Science, Dept. of Chemistry University of Sulaimani
4 Faculty of Sciences and Health,Koya University


Abstract
Silybin is an isomer derived from the seed of Silybum marianum, a biennial metropolitan
plant that is grown naturally in Iraqi Kurdistan Region, it shows antioxidant and
anticancer activity however; its poor water solubility encounters to low bioavailability
which limits its use in clinical practice. To improve water solubility thereby
bioavailability, a chemical derivatization (carboxylic acid) on C-23 (C27H24O12) was
performed. Silybin derivative on C-23 as ether function improves solubility through
increasing the ability to donate unshared electron pairs like Lewis base. The elongated
carbon chain 25 as carboxylic acid increases the polarity of our derivative in water as
well as the acidity. Our derivative was prepared by Williamson method and showed
improvement of water solubility in comparison to silybin; this will lead to enhance the
bioavailability and consequently the activity of the drug. Structure elucidation confirmed
by FTIR, 13C-NMR and mass spectroscopy. The solubility assessment was performed
according to Beer’s-Lambert law.
Aim: Enhance water solubility and bioavailability of silybin through acid derivatization.

Key Words: Silybin, Solubility, Chemical derivatization, Mass-spectroscopy, Bioavailability



References

[1] Hussein I., Khan H., Ali Khan F., Marwat I Kh., Hussein M., Khan L., “Analysis of silymarin and oil contents in the
seeds of Silybum marianum collected from different regions of NWFP Pakistan”, J. Chem. Soc. Pak, 31(6); 921-924,
(2009).
[2] Sabir M.N., and Askari A.A., “Characterization of the flavonolignans in Silybum marianum L. Grown Naturally in
Iraqi-Kurdistan Region”, Journal of Zankoy Sulaimani-Part A (JZS-A), 15(4); 4, (2013).
[3] Tamayo C. and Diamond S., “Review of clinical trials evaluating safety and efficacy of Milk thistle (Silybum
marianum L. Gaertn.)”, Integr Cancer Ther; SAGE publications, 6(2); 146-157, (2007).
[4] Kren V., and Walterova D., “Silybin and silymarin – new effects and applications”, J of Biomed papers, 149(1); 29-
41, (2005).
[5] Pradhan S. C., and Girish C., “Hepatoprotective herbal drug, silymarin from experimental pharmacology to clinical
medicine”, Ind J of Med Res, 124(5); 491-504, (2006).
[6] Wallace S. N., Carrier D. J. and Clausen C., “Batch solvent extraction of flavonolignans from Milk thistle (Silybum
marianum L., Gaertn)”, J of Phytochem anal., 16(1); 7-16, (2005).
[7] Kroll D. J., Shaw H. S., and Oberlies N. H., “Milk thistle nomenclature: Why it matters in cancer research and
pharmacokinetic studies”, J of Integr Cancer Ther. 6(2); 110-119, (2007).
[8] Luper S. N. D., “A review of plants used in the treatment of liver disease: Part 1”, J of altern med rev., 3(6); 410-
421, (1998).
[9] Fraschini F., et al., “Pharmacology of Silymarin”, Clin Drug Invest., 22(1); 51-65, (2002).
[10] Agarwal R, Agarwal C., Ichikawa H., Singh R. P, and Aggarwal B. B, “Anticancer potential of Silymarin: from
bench to bed side”, Anticancer Res., 26(6B); 4457-98, (2006).

[11] Lu W., Lin C., King T. D., Chen H., Reynolds R. C., Li Y., “Silibinin inhibits Wnt/β-catenin signaling by
suppressing Wnt co-receptor LRP6 expression in human prostate and breast cancer cells”, Cellular signaling, Elsevier,
24(12); 2291–2296, (2012).
[12] Deep G., and Agarwal R., “Antimetastatic efficacy of silibinin: molecular mechanisms and therapeutic potential
against cancer”, Cancer Metastasis Rev., Springer Science, 299(3); 447-463, (2010).
[13] Murphy J. M., Caban M., and Kemper K. J., “Milk thistle (Silybum marianum)”, The Longwood Herbal Task
Force., http://www.mcp.edu/herbal/default.htm,1-14. (Feb. 16th 2000).
[14] Yu J., Zhu Y., Wang L., Peng M., Tong Sh., Cao X.., Qui H. and Xu X., “Enhancement of oral bioavailability of
the poorly water-soluble drug silybin by sodium cholate/phospholipid-mixed micelles”, Acta Pharmacologica Sinica.
31; 759–764, (2010).
[15] Javed Sh., Kohli K., Ali M., “Reassessing Bioavailability of Silymarin”, Alternative Medicine Review., 16(3); 239-
249, (2011).
[16] Agarwal Ch., Wadhwa R., Deep G., Biedermann D., Gazak R., Kren V., Agarwal R., “Anti-Cancer Efficacy of
Silybin Derivatives - A Structure-Activity Relationship”, PLOS ONE, 8(3); www.plosone.org., DOI:
10.1371/journal.pone.0060074, (Mar. 2013).
[17] Lam K. S., “New aspects of natural products in drug discovery; a review”, Trends in Microbiology, 15(6); 279–
289, (2007).
[18] Fabre, J.M., “Synthesis Strategies and Chemistry of Nonsymmetrically Substituted Tetrachalcogenafulvalenes”,
Chem. Rev., 104(11); 5133-5150, (2004).
[19] Larsson J., “Methods for measurement of solubility and dissolution rate of sparingly soluble drugs”, MSc thesis,
Dept of Chem Engin, Facul of Eng, Lund University, Sweden, 11-12, (2009).
[20] Betz J. M., Brown B. P.N., Roman C. M. C., “Accuracy, precision, and reliability of chemical measurements in
natural products research Review”, Fitoterapia, Elsevier, 82(1); 44–52, (2011).
[21] Wanga F., Huanga K., Yang L., Gonc J., Tao Q., Li H., Zhaoa Y., Zeng S., Wua X., Stockigt J., Li X., Qua J.,
“Preparation of C-23 esterified silybin derivatives and evaluation of their lipid peroxidation inhibitory and DNA
protective properties”, Bioorganic & Medicinal Chemistry, Elsevier, 17(17); 6380–6389, (2009).
[22] Wudl F. and Nalewajek D., “Preparation of Tetramethyltetraselenafulvalene without the Use of Carbon
Diselenide”, J Chem Soc, Chem Commun, 1(18), 866, (1980).
[23] De Hoffmann E. and Strobant V., “Mass Spectrometry Principles and Applications”, 3rd Ed., John Wiley & Sons,
New York, ISBN 978-0-470-03310-4, 273-275, 282-285. (2007).
[24] McLafferty F., “Turecek. Interpretain of Mass Spectra”, 4th Ed., Mill Valley, University Science Books,
California, ISBN 0-935702-25-3, 13, 371, (1993).
[25] Bai T.-Ch., Zhu J.-J., Zhang H.-L., Huang Ch-G., “Solubility of silybin in aqueous hydrochloric acid solution”,
Fluid Phase Equilibria, Elsevier, 254(1–2), 204–210, (2007).
[26] Yu JN, Zhu Y., Wang L., Peng M., Tong SS., Cao X., Qui H., Xu XM., “Enhancement of oral bioavailability of the
poorly water-soluble drug silybin by sodium cholate/phospholipid-mixed micelles”, Acta Pharmacol Sin. 31(6), 759-64,(2010).
[27] Higuchi T., and Connor K.A., “Phase-solubility techniques”, Advances in analytical chemistry and
instrumentation, 4(1), 117-212, (1965).
[28] Gordaliza M., “Natural products as leads to anticancer drugs”, Clinical and Translational Oncology, 9(12), 767-
776, (2007).

[29] Agrawal P.K. “Studies in Organic Chemistry 39 – Carbon 13-NMR of Flavonoids” 1st Ed., Elsevier,
ISBN: 0444874496 (0-444-87449-6), 77-80, (1989).