Расторопши: семена ранней потенциальных
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- Silymarin - Chemistry and Analogues
IntroductionResearch over the last three decades has provided convincing evidence to support that the diets rich in fruits and vegetables may be protective against the risk of different types of cancers. Of late, several medicinal herbs from plant origin have also received great attention due to their wide range of pharmacological effects. All these dietary agents, medicinal plants and herbs have been tested for their cancer chemopreventive activity. The reduced cancer risk and lack of toxicity associated with high intake of natural products suggest that specific concentrations of phytochemicals from these plant sources may produce cancer chemopreventive effects without causing significant levels of toxicity. Natural agents are believed to suppress the inflammatory process that lead to neoplastic transformation, hyperproliferation, promotion and progression of carcinogenic process and angiogenesis. It is estimated that nearly one-third of all cancer deaths in the United States could be prevented through appropriate dietary modification. Accumulating research evidence suggests that many dietary agents/medicinal plants may be used alone or in combination with traditional chemotherapeutic agents to prevent the occurrence of cancer, their metastatic spread, or even to treat cancer [1,2]. Silymarin has been used for more than 2000 years as a natural remedy for treating hepatitis and cirrhosis and to protect liver from toxic substances. Silymarin acts by antioxidative, anti-lipid peroxidative, antifibrotic, anti-inflammatory, membrane stabilizing, immunomodulatory and liver regenerating mechanisms in experimental liver diseases. Furthermore, silymarin has been extensively studied, both in vivo and in vitro, for its cancer chemopreventive potential against various cancers [3]. This article reviews the current studies regarding various aspects of silymarin as they relate to its efficacy against cancer and associated molecular mechanisms. Silymarin - Chemistry and AnaloguesSilymarin is an active extract from the seeds of the plant milk thistle (Silybum marianum (L.) Gaertn. (Asterceae), and contains approximately 65-80% silymarin flavonolignans (silymarin complex) with small amounts of flavonoids and approximately 20-35% fatty acids and other polyphenolic compounds. The major component of the silymarin complex is silybin that is synonymous with silibinin (Figure 1), together with other flavonolignans namely isosilybin, silychristin, silydianin, and flavonoid taxifolin [4]. Studies have also reported that silybin and isosilybin are the mixture of two diastereoisomers namely silybin A and silybin B and isosilybin A and isosilybin B; the later two are regioisomers of silybin A and silybin B, respectively, from the silymarin mixture [5]. White-flowering varieties of S. marianum contain additional compounds such as 3-deoxyflavanolignans silandrin, silymonin, silyhermin and neosilyhermin A and B [6]. Recently, Mackinnon et al [7] have isolated a new flavonolignan silyamandin from the tincture preparations of the milk thistle fruit. The most commonly utilized silymarin and silibinin products used in clinical trials are Legalon, Thisilyn, Siliphos and Silipide. Silibinin is the most active antihepatotoxic agent in silymarin mixture and contains 1,4-dioxane ring in addition to flavonoid moiety. Ahmed et al [8] have prepared some flavones and coumarins containing the 1,4-dioxane ring system and evaluated them for antihepatotoxic activity against carbon tetrachloride induced hepatotoxicity in albino rats. The compounds 3′, 4′(1″,4″-dioxino) flavone and 3′,4′(2-hydroxy methyl, 1″,4″-dioxino) flavone exhibited a significant activity comparable to standard drug silymarin (silybon-70). Structure activity relationship (SAR) studies revealed that flavonoid analogues containing a hydroxy methyl group at position-2″ in the dioxane ring exhibited superior antihepatotoxic activity in comparison to coumarin derivatives. Varga et al [9] have synthesized structural analogues (flavanone: 2-4 and flavone: 5 and 6) of silybin and tested for inhibitory activity on superoxide anion and protein kinase C (PKC) translocation in phorbol myristate acetate (PMA)-stimulated neutrophils as well as xanthine oxidase activity to identify the molecular structures responsible for the antioxidant property of silybin. It has been shown that different moieties of silybin are involved in the inhibition of overproduction of superoxide anion in stimulated neutrophils, xanthine oxidase activity, and for prevention of hem-mediated oxidative modification of low density lipoproteins (LDL). Gazak et al [10] have prepared carboxylic acid derivatives of silybin and 2,3-dehydrosilybin with improved hydrophilicity. The presence of 2, 3-double bond in the C-ring of flavonoid improved the scavenging/antioxidant potency of the compound. 2,3-dehydrosilybinic acid is a fairly soluble derivative with anti-lipid peroxidation and antiradical activities better than that of silybin. Regarding anti-cancer activity, Dzubak et al [11] have prepared a series of O-alkyl derivatives (methyl and benzyl) of silybin and 2,3-dehydrosilybin and tested for cytotoxicity in multidrug resistant cell lines and the ability to inhibit P-glycoprotein mediated efflux activity. The 3, 7, 20-Tri-O-methyl-2,3-dehydrosilybin was found to be the best inhibitor with relatively low cytotoxicity comparable with that of parent 2,3-dehydrosilybin. More recently, Davis-Searles et al [12] identified seven distinct flavonolignan compound and a flavonoid from commercial silymarin extracts. Among these, four compounds namely silybin A, silybin B, isosilybin A and isosilybin B, showed most consistent anti-proliferative effects in three different human prostate carcinoma LNCaP, DU145 and PC3 cell lines. In further expanding these preliminary observations, recently we have shown that isosilybin B and isosilybin A exert growth inhibition and cell death together with a strong G1 arrest and apoptosis in human prostate carcinoma LNCaP and 22Rv1 cell [13]. Overall, completed studies suggest that the preparations enriched of these two compounds may be preferable for future studies in prostate cancer.
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