(2S,3S,4S,5R,6R)-6-[[(3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-羧基-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-2,3,4a,5,6,7,8,9,10,12,12a,14a-十二氢-1H-苉-3-基]氧基]-3,4,5-三羟基四氢吡喃-2-羧酸 | 34096-83-8

• 物质功能分类: 生物化工 - 提取物 - 植物提取物
• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 中文名称: (2S,3S,4S,5R,6R)-6-[[(3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-羧基-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-2,3,4a,5,6,7,8,9,10,12,12a,14a-十二氢-1H-苉-3-基]氧基]-3,4,5-三羟基四氢吡喃-2-羧酸
• 中文别名: 单葡萄糖醛酸甘草次酸
• 英文名称: glycyrrhetic acid mono-glucuronide
• 英文别名: 3-O-β-D-glucuronopyranosyl glycyrrhetinic acid；prosapogenol；glycyrrhetic acid 3-O-mono-β-D-glucuronide；glycyrrhetic acid-3-O-monoglucuronide；glycyrrhetic acid 3-O-glucuronide；(2S,3S,4S,5R,6R)-6-[[(3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-carboxy-4,4,6a,6b,8a,11,14b-heptamethyl-14-oxo-2,3,4a,5,6,7,8,9,10,12,12a,14a-dodecahydro-1H-picen-3-yl]oxy]-3,4,5-trihydroxyoxane-2-carboxylic acid
• CAS: 34096-83-8
• 化学式: C₃₆H₅₄O₁₀
• 分子量: 646.819
• InChiKey: HLDYLAJAWSKPFZ-QDPIGISRSA-N

物化性质

• 熔点：
  >200oC (dec.)
• 沸点：
  785.0±60.0 °C(Predicted)
• 密度：
  1.31±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  46
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  171
• 氢给体数：
  5
• 氢受体数：
  10

制备方法与用途

概述

单葡萄糖醛酸甘草次酸（GAMG）是甘草酸的一种衍生物，仅含有一分子葡萄糖醛酸，其极性介于甘草酸和甘草次酸之间。相较于甘草酸和甘草次酸，GAMG具有更强的细胞内溶解度和跨膜转运能力，因此拥有更好的生物利用度。近20年来，部分外国学者对GAMG的抗炎、抗过敏及抗癌等生理活性进行了系列实验研究，并对其抗癌功效的作用机制进行了初步探索，证实了18α-GAMG 和 18β-GAMG 都有较强的抗癌作用。因此，开发GAMG作为一种高效新药具有广阔的应用前景。同时，由于其较为安全且作为新型高倍甜味剂的特性，GAMG 在食品添加剂方面的应用也颇具潜力。

制备方法

由于制备GAMG的工艺较为复杂，限制了其广泛应用。筛选出能将甘草酸（GL）特异性水解生产GAMG的新微生物菌株具有重要意义。通过常压室温等离子体（ARTP）诱变后，筛选得到一株蓝状真菌属的有效菌株，并且产率较高，基本上无副产物生成。这不仅为工业化生产GAMG提供了一条新途径，也简化了工艺并降低了生产成本，为后续的放大实验及商业化生产提供了新的思路，为将GAMG应用于食品、医药、化妆品等工业领域奠定了坚实基础。

生物活性

甘草甜素（GL）的重要衍生物——单葡萄糖醛酸甘草次酸（GAMG），不仅具有抗过敏活性，还能够作为甜味剂使用。β-葡糖醛酸糖苷酶（β‐GUS）是关键的 GAMG 产生酶，可以直接将 GL 转化为 GAMG。

体外研究

单葡萄糖醛酸甘草次酸（GAMG）能显著抑制RBL-2H3细胞中β-半乳糖苷酶的释放，其IC50值为0.28 mM。在脂多糖（LPS）诱导的RAW264.7细胞中，GAMG以剂量依赖性方式显著降低硝酸盐浓度，其IC50值为120 μM。

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  甘草酸	glycyrrhizin	1405-86-3	C42H62O16	822.945
  ——	apioglycyrrhizin	121709-66-8	C41H62O14	778.935
  (3beta,20beta)-3-羟基-11-氧代-齐墩果-12-烯-29-酸甲酯	methyl glycyrrhetinate	1477-44-7	C31H48O4	484.72
  甘草次酸	enoxolone	471-53-4	C30H46O4	470.693
  ——	glucuronic acid methyl ester	533934-74-6	C7H12O7	208.168
  ——	benzyl glycyrrhetate	51984-75-9	C37H52O4	560.817
  D-葡萄糖醛酸甲酯 2,3,4-三苯甲酸酯	methyl 2,3,4-tri-O-benzoyl-D-glucopyranuronate	50767-71-0	C28H24O10	520.493
  2,3,4-三-O-苯甲酰基-alpha-D-吡喃葡萄糖醛酸甲酯三氯乙酰亚胺酯	methyl 2,3,4-tri-O-benzoyl-1-O-trichloroacetimidoyl-α-D-glucopyranuronate	169557-99-7	C30H24Cl3NO10	664.88
  ——	methyl 1,2,3,4-tetra-O-benzoyl-β-D-glucopyranuronate	150608-11-0	C35H28O11	624.601

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  ——	glycyrrhetic acid 3-O-mono-β-D-glucuronide	——	C36H54O10	646.819
  甘草次酸	enoxolone	471-53-4	C30H46O4	470.693

反应信息

• 作为反应物：
  描述：

  (2S,3S,4S,5R,6R)-6-[[(3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-羧基-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-2,3,4a,5,6,7,8,9,10,12,12a,14a-十二氢-1H-苉-3-基]氧基]-3,4,5-三羟基四氢吡喃-2-羧酸 在 luminal contents in rat colon 作用下， 以 phosphate buffer 为溶剂， 生成 甘草次酸
  参考文献：
  名称：

  摘要：

  Purpose. The enhancing activity of dipotassium glycyrrhizinate (Grz) on the intestinal absorption of drugs has been demonstrated in an in vitro study using Caco-2 cell monolayers and in an in vivo absorption study in rats.Methods. The hydrolysis of Grz by luminal content and mucosa of the rat colon was investigated. The absorption-enhancing activity of Grz and its hydrolysates was estimated by changes in transepithelial electrical resistance (TEER) and the permeation of sodium fluorescein (Flu-Na) in Caco-7 cell monolayers. It was further evaluated through the absorption of salmon calcitonin (sCT) in the rat colon.Results. Grz was not hydrolyzed to glycyrrhetinylmonoglucuronide (GrMG) and glycyrrhetinic acid (GA) by colonic mucosa, but, rather by the beta-glucuronidase in colonic flora. The hydrolysis of Grz to GrMG was extremely slow and the GrMG produced was rapidly regenerated to GA. Grz and GrMG had no effect on TEER nor on the permeability of Flu-Na across Caco-2 cell monolayers. On the other hand, GA decreased TEER and increased the permeability of Flu-Na in a dose-dependent manner. However, Grz and GrMG enhanced the plasma calcium-lowering effect of sCT after administration in the rat colon. The coadministration of sCT and GA in the rat colon induced the strongest plasma calcium-lowering effect and the highest plasma concentration of sCT.Conclusions. The in vivo enhancing-activity of Grz in the absorption of drugs is dependent on GA, a hydrolysis product of Grz resulting from the action of beta-glucuronidase in intestinal flora.

  DOI：

  10.1023/a:1018822829302
• 作为产物：
  描述：

  甘草次酸 在 三氟甲磺酸三甲基硅酯 、 palladium 10% on activated carbon 、 四丁基溴化铵 、 氢气 、 potassium carbonate 、 potassium hydroxide 作用下， 以 二氯甲烷 、 水 、 乙酸乙酯 、 丙酮 为溶剂， 反应 13.0h， 生成 (2S,3S,4S,5R,6R)-6-[[(3S,4aR,6aR,6bS,8aS,11S,12aR,14aR,14bS)-11-羧基-4,4,6a,6b,8a,11,14b-七甲基-14-氧代-2,3,4a,5,6,7,8,9,10,12,12a,14a-十二氢-1H-苉-3-基]氧基]-3,4,5-三羟基四氢吡喃-2-羧酸
  参考文献：
  名称：

  一种单葡萄糖醛酸甘草次酸的化学合成方法

  摘要：

  本发明公开一种单葡萄糖醛酸甘草次酸的化学合成方法，属于有机合成、药物化学和食品科学领域。以来源丰富、价格低廉的甘草次酸为起始原料，通过对羧基成苄酯，C3羟基与全苯甲酰化的葡萄糖醛酸甲酯糖基给体成苷，再分别脱去甲基、苯甲酰基和苄基共5步反应，简便易行地合成了单葡萄糖醛酸甘草次酸。本发明所用原料和试剂价格便宜，反应条件温和，操作简单，收率理想，为单葡萄糖醛酸甘草次酸的制备提供了可行的化学合成方法。

  公开号：

  CN108948105B

文献信息

• Apioglycyrrhizin and araboglycyrrhizin, two new sweet oleanene-type triterpene oligoglycosides from the root of Glycyrrhiza inflata.
  作者：Isao KITAGAWA、Masahiro SAKAGAMI、Fumi HASHIUCHI、Jun Liang ZHOU、Masayuki YOSHIKAWA、Jiali REN

  DOI：10.1248/cpb.37.551

  日期：——

  Two new sweet oleanene-type triterpene oligoglycosides, named apioglycyrrhizin and araboglycyrrhizin, were isolated from the air-drie root of Glycyrrhiza inflata [Chinese Glycyrrhizae Radix, Shinkyo-kanzo in Japanese], and their structures have been determined on the basis of chemical and physicochemical evidence.

  从胀果甘草（中药名为甘草，日文名为新娇甘）的干燥根中分离出两种新的甘遂型三萜寡糖苷，分别命名为芹菜苷甘草酸和阿拉伯苷甘草酸，并通过化学和物理化学证据确定了它们的结构。
• Synthesis, Molecular Docking and Biological Evaluation of Glycyrrhizin Analogs as Anticancer Agents Targeting EGFR
  作者：Yong-An Yang、Wen-Jian Tang、Xin Zhang、Ji-Wen Yuan、Xin-Hua Liu、Hai-Liang Zhu

  DOI：10.3390/molecules19056368

  日期：——

  Glycyrrhizin (GA) analogs in the form of 3-glucuronides and 18-epimers were synthesized and their anticancer activities were evaluated. Alkaline isomerization of monoglucuronides is reported. In vitro and in vivo studies showed that glycyrrhetinic acid monoglucuronides (GAMGs) displayed higher anticancer activities than those of bisglucuronide GA analogs, while anticancer activity of the 18α-epimer was superior to that of the 18β-epimer. 18α-GAMG was firstly nicely bound to epidermal growth factor receptor (EGFR) via six hydrogen bonds and one charge interaction, and the docking calculation proved the correlation between anticancer activities and EGFR inhibitory activities. Highly active 18α-GAMG is thus of interest for the further studies as a potential anticancer agent.

  合成了3-葡萄糖苷和18-表异构体形式的甘草酸（GA）类似物，并评估了它们的抗癌活性。报道了单葡萄糖苷的碱性异构化。体外和体内研究表明，甘草酸单葡萄糖苷（GAMGs）的抗癌活性优于双葡萄糖苷GA类似物，而18α-表异构体的抗癌活性优于18β-表异构体。18α-GAMG首次通过六个氢键和一个电荷相互作用与表皮生长因子受体（EGFR）良好结合，分子对接计算证明了抗癌活性与EGFR抑制活性之间的相关性。因此，高活性的18α-GAMG作为潜在的抗癌剂值得进一步研究。
• [EN] TRITERPENE GLUCURONIDES AND THEIR USE AS FLAVOR MODIFIERS<br/>[FR] GLUCURONIDES TRITERPÉNIQUES ET LEUR UTILISATION EN TANT QUE MODIFICATEURS D'ARÔME
  申请人：FIRMENICH & CIE

  公开号：WO2021130046A1

  公开（公告）日：2021-07-01

  The present disclosure generally provides triterpene glucuronides, and the use of such compounds and related compounds as flavor modifiers. In some aspects, the disclosure provides certain compositions that include such triterpene glucuronides, such as compositions that include such triterpene glucuronides and one or more other sweeteners. In some other aspects, the disclosure provides methods of reducing the caloric content of a sweetened article, such as a sweetened food or beverage product.

  本发明公开一般提供三萜葡萄糖醛酸苷及其作为风味改良剂的用途。在某些方面，本发明公开提供了包含此类三萜葡萄糖醛酸苷的特定组合物，例如包含此类三萜葡萄糖醛酸苷和一种或多种其他甜味剂的组合物。在其他方面，本发明公开提供了降低加糖物品（如加糖的食品或饮料产品）的卡路里含量的方法。
• Efficient synthesis of glycyrrhetinic acid glycoside/glucuronide derivatives using silver zeolite as promoter
  作者：Maria Carmen del Ruiz Ruiz、Hassan Amer、Christian Stanetty、Igor Beseda、Laszlo Czollner、Priti Shah、Ulrich Jordis、Bernhard Kueenburg、Dirk Claßen-Houben、Andreas Hofinger、Paul Kosma

  DOI：10.1016/j.carres.2009.04.015

  日期：2009.6

  good yields. The ester protecting group located at C-30 of the oleanolic acid scaffold exerted an influence on the overall yield, with the methylester-protected glycosyl acceptor giving better yields compared to the allyl, benzyl as well as diphenylmethyl ester aglycon. The acetyl-protected glucuronides were differently deblocked in high yields via Zemplén deacetylation or via hydrogenolysis followed

  使用糖基溴化物供体和银沸石作为促进剂，以高至高收率和出色的立体选择性合成了甘草次酸的3-O-甘氨酸。除了制备含有β-连接的葡糖基，2-脱氧-2-三氯乙酰氨基-葡糖基，半乳糖基，纤维二糖基和乳糖基残基的糖苷外，还可以将失活的乙酰化的葡糖基吡喃葡萄糖基脲酸酯溴化物供体与三萜糖苷配基酯衍生物良好地偶联。位于齐墩果酸支架的C-30处的酯保护基团对总收率产生影响，与烯丙基，苄基以及二苯基甲基酯糖苷配基相比，由甲基酯保护的糖基受体给出了更好的收率。分别通过Zemplén脱乙酰化或通过氢解，然后通过Zemplén脱乙酰化和碱性水解，分别以高收率对乙酰基保护的葡糖醛酸苷进行解封，以使酯基分别选择性地从葡糖醛酸苷或甘草次酸单元中释放出来。目标糖苷/葡糖醛酸苷用作药物研究的探针，旨在确定糖苷/葡糖醛酸苷三萜的结构-活性关系。
• Saponin and Sapogenol. XLIX. On the Constituents of the Roots of Glycyrrhiza inflata BATALIN from Xinjiang, China. Characterization of Two Sweet Oleanane-Type Triterpene Oligoglycosides, Apioglycyrrhizin and Araboglycyrrhizin.
  作者：Isao KITAGAWA、Kazuyuki HORI、Masahiro SAKAGAMI、Fumi HASHIUCHI、Masayuki YOSHIKAWA、Jiali REN

  DOI：10.1248/cpb.41.1350

  日期：——

  Two sweet oleanane-type triterpene oligoglycosides named apioglycyrrhizin and araboglycyrrhizin were isolated from the air-dried roots of Glycyrrhiza inflata BATALIN, collected in Xinjiang province (Shinkyo-Kanzo in Japanese), together with glycyrrhizin (3), licorice-saponins A3 (8), G2 (10), and H2 (11) and known flavonoid glycosides. On the basis of chemical and physicochemical evidence, the structures of apioglycyrrhizin and araboglycyrrhizin have been determined to be expressed as 3-O-[β-D-apiofuranosyl(1→2)-β-D-glucuronopyranosyl]glycyrrhetic acid (1) and 3-O-[α-L-arabinopyranosyl(1→2)-β-D-glucuronopyranosyl]glycyrrhetic acid (2), respectively.During the course of these studies, it has been found that the hydroxyl groups in the oligosaccharide moiety of the glucuronide saponins may be partially methylated by prolonged treatment with diazomethane in methanol. The sweetness of the saponins hitherto isolated from various Glycyrrhizae Radix has been examined and a structure-sweetness relationship, as compared with glycyrrhizin, has been found.

  从新疆省（日文中的“新疆甘草”）采集的干燥甘草根中分离出两种甜味oleanane型三萜低聚糖苷，分别命名为apioglycyrrhizin和araboglycyrrhizin，同时分离出的还有甘草酸（3）、甘草皂苷A3（8）、G2（10）和H2（11）以及已知黄酮糖苷。根据化学和物理化学证据，确定apioglycyrrhizin和araboglycyrrhizin的结构分别为3-O-[β-D-apiofuranosyl(1→2)-β-D-glucuronopyranosyl]甘草亭酸（1）和3-O-[α-L-arabinopyranosyl(1→2)-β-D-glucuronopyranosyl]甘草亭酸（2）。在进行这些研究的过程中，发现通过在甲醇中长时间处理重氮甲烷，可以使葡萄糖苷皂苷的低聚糖部分中的羟基部分甲基化。对迄今为止从各种甘草根中分离出的皂苷的甜度进行了检测，并发现了与甘草酸相比的结构-甜度关系。