水飞蓟素A,B | 802918-57-6

• 物质功能分类: 分析化学 - 分析试剂 - 离子色谱试剂
• 分子结构分类: 有机化合物 - 木脂素、新木脂素和相关化合物 - 黄酮木脂素
• 中文名称: 水飞蓟素A,B
• 中文别名: 水飞蓟宾A，B（混合物）
• 英文名称: silybin
• 英文别名: silibinin；(2R,3R)-3,5,7-trihydroxy-2-[3-(4-hydroxy-3-methoxyphenyl)-2-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-yl]-2,3-dihydrochromen-4-one
• CAS: 802918-57-6
• 化学式: C₂₅H₂₂O₁₀
• 分子量: 482.444
• InChiKey: SEBFKMXJBCUCAI-DBMPWETRSA-N

物化性质

• 熔点：
  152-153°C
• 沸点：
  793.0±60.0 °C(Predicted)
• 密度：
  1.527±0.06 g/cm3(Predicted)
• 溶解度：
  丙酮（少量，超声处理，加热），DMSO（少量溶解），甲醇（少量，加热）

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  35
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  155
• 氢给体数：
  5
• 氢受体数：
  10

安全信息

• 危险品标志：
  Xi
• 安全说明：
  S26,S37/39
• 危险类别码：
  R36/37/38
• WGK Germany：
  3
• 储存条件：
  Refrigerator

制备方法与用途

黄酮木脂素类化合物

水飞蓟宾属于黄酮木脂素类化合物，是从水飞蓟Silybum marianum (L.) Gaertn.的种子中提取分离得到的一种化合物。它由2种非对映异构体水飞蓟宾A（2R,3R,10R,11R）和水飞蓟宾B（2R,3R,10S,11S）等比例混合组成，具有多种生物活性，尤其突出的是保护肝脏和清除自由基的作用。

性状

水飞蓟宾是一种类白色结晶性粉末，无臭且味微苦涩。它有引湿性，不溶于水，但易溶于稀碱溶液；可溶于丙酮，略溶于甲醇、乙醇，难溶于氯仿。本品系从菊科水飞蓟属植物水飞蓟果实中提取分离的一种黄酮类化合物。

药动学

口服吸收良好，约1.5小时达到峰值。口服后48小时内排出量约为20%，其中80%以代谢物形式由胆汁排出，其余大部分以原形从尿中排出。

药理作用

水飞蓟宾能够稳定肝细胞膜，保护肝细胞的酶系统，并清除肝细胞内的活性氧自由基，从而提高肝脏的解毒能力。实验结果表明，它对四氯化碳、毒蕈碱等肝脏毒物引起的各种类型肝损伤具有不同程度的保护和治疗作用，并对四氯化碳引起的丙氨酸氨基转移酶的升高有一定的阻止作用。

作用机制

水飞蓟宾是一种来自天然植物的类黄酮物质。研究表明，它可以抑制细胞增殖并诱导细胞凋亡，同时具有抗血管生成特性。肿瘤细胞凋亡的诱导是由内质网应激介导的。水飞蓟宾还表现出STAT3靶向抑制剂和AKT活性抑制的作用。

体内研究

在非酒精性脂肪肝病小鼠模型中（C57BL/6J雄性小鼠，6-8周龄），通过每日口服给药4周（剂量为50,100 mg/kg），显著降低了血清和肝脏中的脂质积累。

用途

作为草药产品分析的标准品。

反应信息

• 作为反应物：
  描述：

  水飞蓟素A,B 在 potassium acetate 、 三氟乙酸 作用下， 以 甲醇 、 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 生成 2,3-脱氢水飞蓟宾A
  参考文献：
  名称：

  Inhibition of Aβ Amyloid Growth and Toxicity by Silybins: The Crucial Role of Stereochemistry

  摘要：

  The self-assembling of the amyloid beta (A beta) peptide into neurotoxic aggregates is considered a central event in the pathogenesis of Alzheimer's disease (AD). Based on the "amyloid hypothesis", many efforts have been devoted to designing molecules able to halt disease progression by inhibiting A beta self-assembly. Here, we combine biophysical (ThT assays, TEM and AFM imaging), biochemical (WB and ESI-MS), and computational (all-atom molecular dynamics) techniques to investigate the capacity of four optically pure components of the natural product silymarin (silybin A, silybin B, 2,3-dehydrosilybin A, 2,3-dehydrosilybin B) to inhibit A beta aggregation. Despite TEM analysis demonstrated that all the four investigated flavonoids prevent the formation of mature fibrils, ThT assays, WB and AFM investigations showed that only silybin B was able to halt the growth of small-sized protofibrils thus promoting the formation of large, amorphous aggregates. Molecular dynamics (MD) simulations indicated that silybin B interacts mainly with the C-terminal hydrophobic segment (35)MVGGVV(40) of A beta 40. Consequently to silybin B binding, the peptide conformation remains predominantly unstructured along all the simulations. By contrast, silybin A interacts preferentially with the segments (LVFF20)-L-17 and (27)NKGAI(132) of A beta 40 which shows a high tendency to form bend, turn, and beta-sheet conformation in and around these two domains. Both 2,3-dehydrosilybin enantiomers bind preferentially the segment (LVFF20)-L-17 but lead to the formation of different small-sized, ThT-positive A beta aggregates. Finally, in vivo studies in a transgenic Caenorhabditis elegans strain expressing human A beta indicated that silybin B is the most effective of the four compounds in counteracting A beta proteotoxicity. This study underscores the pivotal role of stereochemistry in determining the neuroprotective potential of silybins and points to silybin B as a promising lead compound for further development in anti-AD therapeutics.

  DOI：

  10.1021/acschemneuro.7b00110
• 作为产物：
  描述：

  23-O-octanoylsilybin 在 Candida antarctica lipase B 、 正丁醇 作用下， 以 甲基叔丁基醚 为溶剂， 反应 29.0h， 生成 水飞蓟素A,B
  参考文献：
  名称：

  Enzymatic Kinetic Resolution of Silybin Diastereoisomers

  摘要：

  In nature, the flavonolignan silybin (1) occurs as a mixture of two diastereomers, silybin A and silybin B, which in a number of biological assays exhibit different activities. A library of hydrolases (lipases, esterases, and proteases) was tested for separating the silybin A and B diastereomers by selective transcsterification or by stereoselective alcoholysis of 23-O-acetylsilybin (2). Novozym 435 proved to be the most suitable enzyme for the preparative production of both optically pure silybins A and B by enzymatic discrimination. Gram amounts of the optically pure substances can be produced within one week, and the new method is robust and readily scalable to tens of grams.

  DOI：

  10.1021/np900758d

文献信息

• Mild and Selective Method of Bromination of Flavonoids
  作者：Martina Hurtová、David Biedermann、Marek Kuzma、Vladimír Křen

  DOI：10.1021/acs.jnatprod.0c00655

  日期：2020.11.25

  in good yields using α,β-dibromohydrocinnamic acid in the presence of a base. This procedure enables selective mono- or dibromination of compounds highly sensitive to oxidative or radical attack. New brominated derivatives of silymarin flavonolignans and related flavonoids were prepared. These brominated derivatives can be used as valuable synthetic intermediates in further synthesis.

  开发了一种在碱存在下使用 α,β-二溴氢化肉桂酸以良好收率温和选择性溴化简单芳香族化合物和黄酮类化合物的新方法。该程序能够对氧化或自由基攻击高度敏感的化合物进行选择性单溴化或二溴化。制备了水飞蓟素黄酮木脂素和相关黄酮类化合物的新型溴化衍生物。这些溴化衍生物可在进一步合成中用作有价值的合成中间体。
• Glycosylation of silybin
  作者：Vladimír Křen、Jiří Kubisch、Petr Sedmera、Petr Halada、Věra Přikrylová、Alexandr Jegorov、Ladislav Cvak、Rolf Gebhardt、Jitka Ulrichová、Vilím Šimánek

  DOI：10.1039/a703283h

  日期：——

  Silybin glycosides—23-O-β-glucoside 2b, β-galactoside 3b, β-lactoside 4b and β-maltoside 5b—have been synthesized by different methods (Helferich glycosylation, Lewis acid catalysis). Separation of two silybin diastereoisomers in the form of acetylated monoglycosides has been achieved for the first time. These new silybin glycosides are 4–30 times more water-soluble, and their hepatoprotectivity is increased compared with that of the parent compound silybin 1.

  西利宾糖苷——23-O-β-葡萄糖苷2b、β-半乳糖苷3b、β-乳糖苷4b和β-麦芽糖苷5b——通过不同的方法合成（赫尔费里希糖基化、路易斯酸催化）。首次实现了以乙酰化单糖苷形式分离两种西利宾的消旋异构体。这些新的西利宾糖苷的水溶性提高了4-30倍，其保护肝脏的能力相比于母体化合物西利宾1也有所增强。
• O-Aminoalkyl-O-Trimethyl-2,3-Dehydrosilybins: Synthesis and In Vitro Effects Towards Prostate Cancer Cells
  作者：Bao Vue、Sheng Zhang、Andre Vignau、Guanglin Chen、Xiaojie Zhang、William Diaz、Qiang Zhang、Shilong Zheng、Guangdi Wang、Qiao-Hong Chen

  DOI：10.3390/molecules23123142

  日期：——

  As part of our ongoing silybin project, this study aims to introduce a basic nitrogen-containing group to 7-OH of 3,5,20-O-trimethyl-2,3-dehydrosilybin or 3-OH of 5,7,20-O-trimethyl-2,3-dehydrosilybin via an appropriate linker for in vitro evaluation as potential anti-prostate cancer agents. The synthetic approaches to 7-O-substituted-3,5,20-O-trimethyl-2,3-dehydrosilybins through a five-step procedure and to 3-O-substituted-5,7,20-O-trimethyl-2,3- dehydrosilybins via a four-step transformation have been developed. Thirty-two nitrogen-containing derivatives of silybin have been achieved through these synthetic methods for the evaluation of their antiproliferative activities towards both androgen-sensitive (LNCaP) and androgen-insensitive prostate cancer cell lines (PC-3 and DU145) using the WST-1 cell proliferation assay. These derivatives exhibited greater in vitro antiproliferative potency than silibinin. Among them, 11, 29, 31, 37, and 40 were identified as five optimal derivatives with IC50 values in the range of 1.40–3.06 µM, representing a 17- to 52-fold improvement in potency compared to silibinin. All these five optimal derivatives can arrest the PC-3 cell cycle in the G0/G1 phase and promote PC-3 cell apoptosis. Derivatives 11, 37, and 40 are more effective than 29 and 31 in activating PC-3 cell apoptosis.

  作为我们正在进行的水飞蓟素项目的一部分，这项研究旨在通过适当的连接剂将一种含氮基团引入3,5,20-O-三甲基-2,3-脱氢水飞蓟素的7-OH位置或者5,7,20-O-三甲基-2,3-脱氢水飞蓟素的3-OH位置，以进行体外评估作为潜在的抗前列腺癌药物。通过五步法合成了7-O取代的3,5,20-O-三甲基-2,3-脱氢水飞蓟素，通过四步转化合成了3-O取代的5,7,20-O-三甲基-2,3-脱氢水飞蓟素。通过这些合成方法，已经合成了32种含氮衍生物的水飞蓟素，用于评估它们对雄激素敏感（LNCaP）和雄激素非敏感前列腺癌细胞系（PC-3和DU145）的抗增殖活性，使用WST-1细胞增殖测定法。这些衍生物在体外表现出比水飞蓟素更强的抗增殖活性。其中，11、29、31、37和40被确定为五种优化的衍生物，其IC50值在1.40-3.06 µM范围内，与水飞蓟素相比，其效力提高了17-52倍。所有这五种优化的衍生物都能使PC-3细胞周期停滞在G0/G1期，并促进PC-3细胞凋亡。衍生物11、37和40在激活PC-3细胞凋亡方面比29和31更有效。
• New C-23 modified of silybin and 2,3-dehydrosilybin: Synthesis and preliminary evaluation of antioxidant properties
  作者：Armando Zarrelli、Alessandro Sgambato、Valentina Petito、Lorenzo De Napoli、Lucio Previtera、Giovanni Di Fabio

  DOI：10.1016/j.bmcl.2011.06.049

  日期：2011.8

  Furthermore a new and efficient method for the preparation of DHS from silybin was developed and optimised. The antioxidant properties of the new compounds were evaluated in a cellular model in vivo and they displayed an antioxidant activity comparable to or higher than silybin and DHS, being able to prevent H2O2-induced generation of intracellular reactive oxygen species (ROS). Most of the derivatives also

  水飞蓟宾是水飞蓟素的主要黄酮木脂素，它具有多种生物学效应，通常归因于其抗氧化性能。本文中，我们将描述一种有效的合成策略，以使用以下方法获得各种新的和更水溶性的水飞蓟宾和2,3-脱氢水飞蓟宾（DHS）衍生物，其中23-羟基被转化为硫酸盐，磷酸二酯或胺基解决方案阶段的方法。此外，开发和优化了一种新的，高效的从水飞蓟宾制备DHS的方法。 在体内细胞模型中评估了新化合物的抗氧化性能，它们显示出的抗氧化活性与水飞蓟宾和DHS相当或更高，能够防止H 2 O 2诱导的细胞内活性氧（ROS）生成。大多数衍生物还表现出更好的亲水性，同时保留了水飞蓟宾的生物活性，它们可能会拓宽此类天然化合物的体内应用范围。
• Unconventional application of the Mitsunobu reaction: Selective flavonolignan dehydration yielding hydnocarpins
  作者：Guozheng Huang、Simon Schramm、Jörg Heilmann、David Biedermann、Vladimír Křen、Michael Decker

  DOI：10.3762/bjoc.12.66

  日期：——

  Various Mitsunobu conditions were investigated for a series of flavonolignans (silybin A, silybin B, isosilybin A, and silychristin A) to achieve either selective esterification in position C-23 or dehydration in a one-pot reaction yielding the biologically important enantiomers of hydnocarpin D, hydnocarpin and isohydnocarpin, respectively. This represents the only one-pot semi-synthetic method to

  研究了各种Mitsunobu条件下的一系列黄酮木聚糖（水飞蓟宾A，水飞蓟宾B，异水飞蓟宾A和水飞蓟素A），以实现C-23位置的选择性酯化或一锅反应脱水，从而制得Hydnocarpin D的生物学上重要的对映异构体，hydnocarpin和isohydnocarpin。这代表了以高产率获得这些黄酮木聚糖的唯一的一锅法半合成方法。