Synthesis and antiangiogenic activity of new silybin galloyl esters.

The synthesis of various silybin monogalloyl esters was developed, and their antiangiogenic activities were evaluated in a variety of in vitro tests with human umbilical vein endothelial cells (HUVECs). A structure-activity relationship (SAR) study found the regioselectivity of the silybin galloylation to be highly significant. Silybin (as an equimolar mixture of two diastereomers A and B) exhibited quite poor antiangiogenic activities, whereas its B stereoisomer is more active than silybin A. The galloylation of phenolic OH groups of natural silybin (a mixture of both isomers) leads to increases in their antiangiogenic activities, which is more apparent with the 7-OH than the 20-OH. In contrast, gallates at aliphatic OH groups either had a comparable activity to the parent compound or are even worse than silybin, which was observed in the case of 3-O-galloylsilybin. The most effective compound from this series (7-O-galloylsilybin) has also been prepared from stereochemically pure silybins A and B to evaluate the effect of stereochemistry on the activity. As with silybin itself, the B isomer of 7-O-galloylsilybin was more active than the A isomer.

[1]  V. Křen,et al.  Narrow-bore core-shell particles and monolithic columns in the analysis of silybin diastereoisomers. , 2011, Journal of separation science.

[2]  V. Křen,et al.  Large-scale separation of silybin diastereoisomers using lipases , 2010 .

[3]  P. Ferenci,et al.  Successful HCV eradication and inhibition of HIV replication by intravenous silibinin in an HIV-HCV coinfected patient. , 2010, Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology.

[4]  R. Agarwal,et al.  Antimetastatic efficacy of silibinin: molecular mechanisms and therapeutic potential against cancer , 2010, Cancer and Metastasis Reviews.

[5]  R. Agarwal,et al.  Silibinin Exerts Sustained Growth Suppressive Effect against Human Colon Carcinoma SW480 Xenograft by Targeting Multiple Signaling Molecules , 2010, Pharmaceutical Research.

[6]  V. Křen,et al.  Enzymatic kinetic resolution of silybin diastereoisomers. , 2010, Journal of natural products.

[7]  V. Křen,et al.  Antioxidant and antiviral activities of silybin fatty acid conjugates. , 2010, European journal of medicinal chemistry.

[8]  R. Agarwal,et al.  Silibinin inhibits human nonsmall cell lung cancer cell growth through cell‐cycle arrest by modulating expression and function of key cell‐cycle regulators , 2010, Molecular carcinogenesis.

[9]  S. Zeng,et al.  Preparation of C-23 esterified silybin derivatives and evaluation of their lipid peroxidation inhibitory and DNA protective properties. , 2009, Bioorganic & medicinal chemistry.

[10]  V. Křen,et al.  Molecular mechanisms of silybin and 2,3-dehydrosilybin antiradical activity--role of individual hydroxyl groups. , 2009, Free radical biology & medicine.

[11]  V. Křen,et al.  Enzymatic preparation of acylated derivatives of silybin in organic and ionic liquid media and evaluation of their antitumor proliferative activity , 2009 .

[12]  G. Owen,et al.  A semi-quantitative assay to screen for angiogenic compounds and compounds with angiogenic potential using the EA.hy926 endothelial cell line. , 2009, Biological research.

[13]  R. Agarwal,et al.  Silibinin Inhibits Established Prostate Tumor Growth, Progression, Invasion, and Metastasis and Suppresses Tumor Angiogenesis and Epithelial-Mesenchymal Transition in Transgenic Adenocarcinoma of the Mouse Prostate Model Mice , 2008, Clinical Cancer Research.

[14]  R. Agarwal,et al.  Identifying the differential effects of silymarin constituents on cell growth and cell cycle regulatory molecules in human prostate cancer cells , 2008, International journal of cancer.

[15]  V. Křen,et al.  Mechanism of the antioxidant action of silybin and 2,3-dehydrosilybin flavonolignans: a joint experimental and theoretical study. , 2008, The journal of physical chemistry. A.

[16]  V. Křen,et al.  Silybin and silymarin--new and emerging applications in medicine. , 2007, Current medicinal chemistry.

[17]  B. Aggarwal,et al.  Anticancer potential of silymarin: from bench to bed side. , 2006, Anticancer research.

[18]  Xiaofei Zhang,et al.  Preparation of tritium‐labeled Silybin—a protectant for common liver diseases , 2006 .

[19]  V. Křen,et al.  New derivatives of silybin and 2,3-dehydrosilybin and their cytotoxic and P-glycoprotein modulatory activity. , 2006, Bioorganic & medicinal chemistry.

[20]  V. Křen,et al.  Effects of silymarin flavonolignans and synthetic silybin derivatives on estrogen and aryl hydrocarbon receptor activation. , 2005, Toxicology.

[21]  M. Medina,et al.  Hypericin in the dark inhibits key steps of angiogenesis in vitro. , 2005, European journal of pharmacology.

[22]  R. Agarwal,et al.  Milk thistle and prostate cancer: differential effects of pure flavonolignans from Silybum marianum on antiproliferative end points in human prostate carcinoma cells. , 2005, Cancer research.

[23]  R. Agarwal,et al.  Silibinin strongly inhibits growth and survival of human endothelial cells via cell cycle arrest and downregulation of survivin, Akt and NF-κB: implications for angioprevention and antiangiogenic therapy , 2005, Oncogene.

[24]  Yuji Saito,et al.  Ester synthesis from α-substituted carboxylic acid catalyzed by polyethylene glycol-modified lipase fromCandidacylindracea in benzene , 1986, Biotechnology Letters.

[25]  V. Křen,et al.  Oxidised derivatives of silybin and their antiradical and antioxidant activity. , 2004, Bioorganic & medicinal chemistry.

[26]  M. Ghoul,et al.  Enzymatic synthesis of new aromatic and aliphatic esters of flavonoids using Candida antarctica lipase as biocatalyst , 2004 .

[27]  J. Graille,et al.  Esterification of phenolic acids from green coffee with an immobilized lipase from Candida antarctica in solvent-free medium , 1997, Biotechnology Letters.

[28]  D. Y. Lee,et al.  Molecular structure and stereochemistry of silybin A, silybin B, isosilybin A, and isosilybin B, Isolated from Silybum marianum (milk thistle). , 2003, Journal of natural products.

[29]  Nam-Cheol Kim,et al.  Complete isolation and characterization of silybins and isosilybins from milk thistle (Silybum marianum). , 2003, Organic & biomolecular chemistry.

[30]  S. B. Sawant,et al.  Lipolase catalyzed synthesis of benzyl esters of fatty acids , 2002 .

[31]  K. Kaji,et al.  Tea catechins inhibit angiogenesis in vitro, measured by human endothelial cell growth, migration and tube formation, through inhibition of VEGF receptor binding. , 2002, Cancer letters.

[32]  Z. Zhang,et al.  Determination of active component in silymarin by RP-LC and LC/MS. , 2001, Journal of pharmaceutical and biomedical analysis.

[33]  U. Bornscheuer,et al.  Substrate specificity of lipase B from Candida antarctica in the synthesis of arylaliphatic glycolipids , 2000 .

[34]  H. de Groot,et al.  Scavenging of reactive oxygen species and inhibition of arachidonic acid metabolism by silibinin in human cells. , 1996, Life sciences.

[35]  J. Foekens,et al.  The MTT Tetrazolium Salt Assay Scrutinized: How to Use this Assay Reliably to Measure Metabolie Activity of Cell Cultures in vitro for the Assessment of Growth Characteristics, IC50-Values and Cell Survival , 1995, European journal of clinical chemistry and clinical biochemistry : journal of the Forum of European Clinical Chemistry Societies.

[36]  Y. Tamaura,et al.  Modified lipoprotein lipase catalyzes ester synthesis in benzene. Substrate specificity. , 1984, Enzyme.