[（3R，3aS，4S，8aR）-3-羟基-6,8a-二甲基-3-丙-2-基-1,2,3a，4,5,8-六氢azulen-4-基]4-羟基苯甲酸酯 | 41743-44-6

• 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: [（3R，3aS，4S，8aR）-3-羟基-6,8a-二甲基-3-丙-2-基-1,2,3a，4,5,8-六氢azulen-4-基]4-羟基苯甲酸酯
• 英文名称: ferutinin
• 英文别名: jaeschkeanadiol p-hydroxybenzoate；ferutinine；[(3R,3aS,4S,8aR)-3-hydroxy-6,8a-dimethyl-3-propan-2-yl-1,2,3a,4,5,8-hexahydroazulen-4-yl] 4-hydroxybenzoate
• CAS: 41743-44-6
• 化学式: C₂₂H₃₀O₄
• 分子量: 358.478
• InChiKey: CYSHNJQMYORNJI-YUVXSKOASA-N

物化性质

• 沸点：
  489.0±45.0 °C(Predicted)
• 密度：
  1.16±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO
• LogP：
  5.720 (est)

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  26
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  66.8
• 氢给体数：
  2
• 氢受体数：
  4

制备方法与用途

Ferutinin是一种天然萜类化合物，是雌激素受体ERα激动剂和雌激素ERβ受体激动剂/拮抗剂，IC50值分别为33.1 nM和180.5 nM。阿魏苷作为一种电生钙离子载体，能够增加脂质双层膜及线粒体的钙通透性。Ferutinin具有雌激素、抗肿瘤、抗菌以及抗炎活性。

反应信息

• 作为反应物：
  描述：

  [（3R，3aS，4S，8aR）-3-羟基-6,8a-二甲基-3-丙-2-基-1,2,3a，4,5,8-六氢azulen-4-基]4-羟基苯甲酸酯 在 potassium hydroxide 作用下， 反应 2.0h， 生成 反式-4-甲基-1-(乙氧羰基)环己烷
  参考文献：
  名称：

  Synthesis and in vitro evaluation of ferutinol aryl esters for estrogenic activity and affinity toward cannabinoid receptors

  摘要：

  Ferutinin (1), the major constituent of Ferula hermonis and other Ferula species, is a sesquiterpene ester with remarkable estrogenic activity, beside other valuable medicinal properties. To investigate the influence of chemical modification of the ferutinin structure on its estrogenic effect and binding affinity toward the cannabinoid CB1 and CB2 receptors, twelve derivatives of 1 were prepared and evaluated in vitro, together with the parent compound, for the respective bioactivities, based on the recent evidence for estrogen-endocannabinoid interaction. Nine of the prepared derivatives (3-11) are new semisynthetic esters of 1. The parent compound ferutinin (1) exhibited the highest level of estrogenic activity (EC50 0.3 mu M and a percent maximal 17 beta-estradiol response of 90 % at 1 A mu M). Compound 6 was found to be a selective agonist for CB2 receptor (EC50 0.051 mu M, Ki 0.025 mu M), with much less affinity for CB1 receptor (EC50 97 mu M, Ki 48.5 mu M). Compound 8 was a selective agonist for CB1 (EC50 62, Ki 0.031 mu M) with no affinity toward CB2.

  DOI：

  10.1007/s00044-015-1319-7
• 作为产物：
  描述：

  4-acetoxybenzoyl chloride 在 吡啶 、 potassium carbonate 作用下， 以 甲醇 为溶剂， 反应 12.0h， 生成 [（3R，3aS，4S，8aR）-3-羟基-6,8a-二甲基-3-丙-2-基-1,2,3a，4,5,8-六氢azulen-4-基]4-羟基苯甲酸酯
  参考文献：
  名称：

  Tolstikov, G. A.; Akbutina, F. A.; Dembitskii, A. D., Journal of Organic Chemistry USSR (English Translation), 1992, vol. 28, # 10, p. 1666 - 1673

  摘要：

  DOI：

文献信息

• Structure−Activity Relationships of the Estrogenic Sesquiterpene Ester Ferutinin. Modification of the Terpenoid Core
  作者：Giovanni Appendino、Paola Spagliardi、Olov Sterner、Stuart Milligan

  DOI：10.1021/np049796w

  日期：2004.9.1

  Esterification of p-hydroxybenzoic acid, a very weak estrogenic compound, with the daucane alcohol jaeschkeanadiol (1b) leads to a spectacular magnification of the estrogenic activity. To identify the structural elements responsible for this effect, the terpenoid core of jaeschkeanadiol p-hydroxybenzoate (ferutinin, 1a) was modified, capitalizing on the presence of two functionalities, the monoacylated, hydrogen-bonded 1,3-diol system and the double bond. The hydrogen bonding, while possibly useful, was not critical for activity, while hydrogenation and cyclopropanation of the double bond were tolerated. Conversely, oxidative modifications of the double bond that placed a hydroxyl on the a-face of the molecule proved detrimental. Taken together, these observations identified the substitution at C-8/C-9 as critical for activity.
• Hemisynthesis, Antitumoral Effect, and Molecular Docking Studies of Ferutinin and Its Analogues
  作者：Rémi Safi、Fréderic Rodriguez、Georges Hilal、Mona Diab-Assaf、Youssef Diab、Marwan El-Sabban、Fadia Najjar、Evelyne Delfourne

  DOI：10.1111/cbdd.12670

  日期：2016.3

  The natural product ferutinin was shown to act as an agonist to estrogen receptor ERα and agonist/antagonist to ERβ featuring a weak antiproliferative activity toward breast cancer cells. To enhance this activity, ferutinin analogues were synthesized by esterification of jaeschkenadiol with different acids. These compounds were assayed for their in vitro antiproliferative activity against estrogen‐dependent (MCF‐7) and estrogen‐independent (MDA‐MB‐231) breast cancer cell lines. Among the compounds, 3c’ exhibited a potent inhibitory selective activity against MCF‐7 with IC50 value of 1 μm. Docking simulation of 3c’ in the ligand binding domain of the ERs indicated a potential antagonism interaction with both ER subtypes. Functional assay showed that 3c’ binds as an antagonist to ERα protein while ferutinin acts as an agonist.
• Daucane Phytoestrogens:  A Structure−Activity Study
  作者：Giovanni Appendino、Paola Spagliardi、Giancarlo Cravotto、Victoria Pocock、Stuart Milligan

  DOI：10.1021/np0201671

  日期：2002.11.1

  The estrogenic activity of a series of analogues of the daucane ester ferutinin (1a) modified at the acyl moiety was investigated in a yeast screen containing the human estrogen receptor a. Rather strict structure-activity relationships were observed. Thus, while the parent polvol (jaeschkeanadiol, 2a) was inactive, the presence of a p-hydroxybenzoyl moiety was necessary for activity in the yeast screen. Homologation and vinylation were both detrimental for activity, as were methylation of the p-hydroxyl substituent and the introduction of oxygen functions on the adjacent carbons.
• Antimycobacterial activity of ferutinin alone and in combination with antitubercular drugs against a rapidly growing surrogate of<i>Mycobacterium tuberculosis</i>
  作者：Ehab A. Abourashed、Ahmed M. Galal、Atef M. Shibl

  DOI：10.1080/14786419.2010.481623

  日期：2011.7

  The aim of this study was to investigate the antimycobacterial activity of the major daucane constituent, ferutinin (jaeschkeandiol p-hydroxybenzoate, 1), four of its natural analogues, its hydrolysis products, as well as methyl p-hydroxybenzoate (methylparaben) against Mycobacterium smegmatis, a rapidly growing surrogate of Mycobacterium tuberculosis. The agar dilution assay was utilised for an antimycobacterial evaluation of single compounds. A modified agar dilution assay, the checkerboard method, was utilised for evaluating the potentiating effect of 1 on different antitubercular drugs, namely isoniazid, ethionamide, rifampin and streptomycin. In the agar dilution assay, 1 exhibited higher potency (minimum inhibitory concentration [MIC] 10 mu g mL(-1)) than streptomycin and rifampin (MIC 20 mu g mL(-1) for each). Of the natural analogues, 8,9-epoxyjaeschkeandiol p-hydroxybenzoate and 8,9-epoxyjaeschkeandiol benzoate exhibited marginal activity (MIC >= 40 and 80 mg mL(-1), respectively). The checkerboard method showed that the combination of 1 with each antitubercular drug led to mutual enhancement of the antimycobacterial activity with isoniazid and ethionamide, while no such effect was observed with rifampin or streptomycin. Based on this study and earlier studies with Staphylococcus aureus, the major constituent 1 may be responsible for the major part of the antimicrobial activity of the root of Ferula hermonis.
• AHMED, AHMED A., J. NATUR. PROD., 53,(1990) N, C. 483-486
  作者：AHMED, AHMED A.

  DOI：——

  日期：——