1,3,5(10)-雌二醇-3,4,17beta-三醇 4-甲醚 | 26788-23-8

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 中文名称: 1,3,5(10)-雌二醇-3,4,17beta-三醇 4-甲醚
• 中文别名: 1,3,5(10)-雌二醇-3,4,17beta-三醇4-甲醚；4-甲氧基-17Beta-雌二醇；2-溴Mo-2-甲基-d3-丙酸乙酯-3,3,3-d3
• 英文名称: 4-methoxy-17β-estradiol
• 英文别名: 4-Methoxyestradiol；3-hydroxy-4-methoxyestra-1,3,5(10)-trien-17β-ol；4-methoxyestradiol-17β；(8R,9S,13S,14S,17S)-4-methoxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthrene-3,17-diol
• CAS: 26788-23-8
• 化学式: C₁₉H₂₆O₃
• 分子量: 302.414
• InChiKey: BCWZIZLVBYHFES-PYEWSWHRSA-N

物化性质

• 熔点：
  165-167°C
• 沸点：
  472.0±45.0 °C(Predicted)
• 密度：
  1.178±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（轻微超声处理）、甲醇
• 物理描述：
  Solid

计算性质

• 辛醇/水分配系数(LogP)：
  4
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.68
• 拓扑面积：
  49.7
• 氢给体数：
  2
• 氢受体数：
  3

制备方法与用途

4-甲氧基 Estradiol 是一种可诱导人肺上皮细胞发生氧化性 DNA 损伤的物质，还能在 H1355 细胞中增加 ROS 和 SOD 的活性。

反应信息

• 作为反应物：
  描述：

  1,3,5(10)-雌二醇-3,4,17beta-三醇 4-甲醚 在 N-溴代丁二酰亚胺(NBS) 作用下， 以 溶剂黄146 为溶剂， 反应 0.5h， 以3%的产率得到2-bromo-4-methoxyestra-1,3,5(10)-triene-3,17β-diol
  参考文献：
  名称：

  Pert, Derek J.; Ridley, Damon D., Australian Journal of Chemistry, 1989, vol. 42, # 3, p. 421 - 432

  摘要：

  DOI：
• 作为产物：
  描述：

  2,4-diiodoestra-1,3,5(10)-triene-3,17β-diol 在 5% Pd on active carbon 氢气 、 copper dichloride 作用下， 以 甲醇 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 0.08h， 生成 1,3,5(10)-雌二醇-3,4,17beta-三醇 4-甲醚
  参考文献：
  名称：

  Numazawa, Mitsuteri; Ogura, Yuko; Kimura, Katsuhiko, Journal of Chemical Research, Miniprint, 1985, # 11, p. 3701 - 3715

  摘要：

  DOI：

文献信息

• Efficient synthesis of 2-methoxy- and 4-methoxy-estrogens
  作者：Mitsuteru Numazawa、Yuko Ogura

  DOI：10.1039/c39830000533

  日期：——

  2-Methoxy- and 4-methoxy-estrogens are easily prepared from the corresponding 2-iodo or 4-bromo derivatives in high yields by a halogen–methoxy group exchange reaction using sodium methoxide–copper(II) chloride.

  通过使用甲醇钠-氯化铜（II）进行卤素-甲氧基交换反应，可以轻松地从相应的2-碘或4-溴衍生物以高收率制备2-甲氧基-和4-甲氧基-雌激素。
• A new synthetic route to 2- and 4-methoxyestradiols by nucleophilic substitution
  作者：Shu-hua Chen、Guan-rong Luo、Xu-sen Wu、Min Chen、Hua-ming Zhao

  DOI：10.1016/0039-128x(86)90077-2

  日期：1986.1

  A new snythetic route to 2- and 4-methoxyestradiols is described. Benzo-15-crown-5 with CuI catalyzes the specific nucleophilic substitution at the carbon atom carrying a non-activated halogen on ring A of the estradiol.

  描述了一种新的2-和4-甲氧基雌二醇的合成途径。具有CuI的Benzo-15-crown-5催化在雌二醇A环上携带未活化卤素的碳原子上的特定亲核取代。
• Methylation of Catechol Estrogen with Diazomethane
  作者：MASANORI TERANISHI、YOUICHI FUJII、MITSURU YAMAZAKI、SUSUMU MIYABO

  DOI：10.1248/cpb.31.3309

  日期：——

  Dynamic aspects of methylation of catechol estrogen with diazomethane were investigated by means of thin-layer chromatography. The methylation rate of the hydroxyl group at the C-3 position was almost the same as that of the C-2 hydroxyl group in the reaction of 2-hydroxyestrogen, and 2-3 times that of the C-4 hydroxyl group in the reaction of 4-hydroxyestrogen. In these experiments, the maximum yields of 2-methoxyestrone, 2-hydroxyestrone 3-methyl ether, 4-methoxyestrone and 4-hydroxyestrone 3-methyl ether were 32, 39, 13 and 70%, respectively. In addition, demethylation of catechol estrogen dimethyl ethers with boron tribromide and synthesis of 4-hydroxyestrone monomethyl ethers are described.

  通过薄层色谱法研究了二氮甲烷与邻苯二酚雌激素的甲基化反应的动态过程。在2-羟基雌激素反应中，C-3位置的羟基甲基化速率几乎与C-2羟基相同，而在4-羟基雌激素反应中，C-3羟基的甲基化速率是C-4羟基的2-3倍。在这些实验中，2-甲氧基雌酮、2-羟基雌酮3-甲基醚、4-甲氧基雌酮和4-羟基雌酮3-甲基醚的最高产率分别为32%、39%、13%和70%。此外，还描述了用三溴化硼脱除邻苯二酚雌激素二甲基醚的甲基化和4-羟基雌酮单甲基醚的合成。
• Lack of Cell Proliferative and Tumorigenic Effects of 4-Hydroxyestradiol in the Anterior Pituitary of Rats: Role of Ultrarapid <i>O</i>-Methylation Catalyzed by Pituitary Membrane-Bound Catechol-<i>O</i>-Methyltransferase
  作者：Pan Wang、Laura H. Mills、Ji-Hoon Song、Jina Yu、Bao-Ting Zhu

  DOI：10.1021/acs.chemrestox.7b00096

  日期：2017.7.17

  In animal models, estrogens are complete carcinogens in certain target sites. 4-Hydroxyestradiol (4-OH-E2), an endogenous metabolite of 17β-estradiol (E2), is known to have prominent estrogenic activity plus potential genotoxicity and mutagenicity. We report here our finding that 4-OH-E2 does not induce pituitary tumors in ACI female rats, whereas E2 produces 100% pituitary tumor incidence. To probe the mechanism, we conducted a short-term animal experiment to compare the proliferative effect of 4-OH-E2 in several organs. We found that, whereas 4-OH-E2 had little ability to stimulate pituitary cell proliferation in ovariectomized female rats, it strongly stimulates cell proliferation in certain brain regions of these animals. Further, when we used in vitro cultured rat pituitary tumor cells as models, we found that 4-OH-E2 has similar efficacy as E2 in stimulating cell proliferation, but its potency is approximately 3 orders of magnitude lower than that of E2. Moreover, we found that the pituitary tumor cells have the ability to selectively metabolize 4-OH-E2 (but not E2) with ultrahigh efficiency. Additional analysis revealed that the rat pituitary expresses a membrane-bound catechol-O-methyltransferase that has an ultralow Km value (in nM range) for catechol estrogens. On the basis of these observations, it is concluded that rapid metabolic disposition of 4-OH-E2 through enzymatic O-methylation in rat anterior pituitary cells largely contributes to its apparent lack of cell proliferative and tumorigenic effects in this target site.

  在动物模型中，雌激素是某些靶点的完全致癌物。众所周知，4-羟基雌二醇（4-OH-E2）是 17β-雌二醇（E2）的内源性代谢产物，具有显著的雌激素活性和潜在的遗传毒性和致突变性。我们在此报告我们的发现：4-OH-E2 不会诱发 ACI 雌性大鼠的垂体瘤，而 E2 则会产生 100% 的垂体瘤发病率。为了探究其机制，我们进行了一项短期动物实验，比较 4-OH-E2 在多个器官中的增殖效应。我们发现，4-OH-E2 对切除卵巢的雌性大鼠的垂体细胞增殖几乎没有刺激作用，但却能强烈刺激这些动物某些脑区的细胞增殖。此外，当我们使用体外培养的大鼠垂体瘤细胞作为模型时，我们发现 4-OH-E2 在刺激细胞增殖方面具有与 E2 相似的功效，但其效力比 E2 低约 3 个数量级。此外，我们还发现垂体瘤细胞能够选择性地超高效率代谢 4-OH-E2（而非 E2）。其他分析表明，大鼠垂体表达一种膜结合儿茶酚-O-甲基转移酶，该酶对儿茶酚雌激素的 Km 值极低（在 nM 范围内）。根据这些观察结果，可以得出结论：4-OH-E2 在大鼠垂体前叶细胞中通过酶促 O-甲基化作用迅速代谢，这在很大程度上导致了它在这一靶点明显缺乏细胞增殖和致瘤效应。
• Specificity and Regioselectivity of the Conjugation of Estradiol, Estrone, and Their Catecholestrogen and Methoxyestrogen Metabolites by Human Uridine Diphospho-glucuronosyltransferases Expressed in Endometrium
  作者：Johanie Lépine、Olivier Bernard、Marie Plante、Bernard Têtu、Georges Pelletier、Fernand Labrie、Alain Bélanger、Chantal Guillemette

  DOI：10.1210/jc.2004-0331

  日期：2004.10.1

  Uridine diphospho-glucuronosyltransferases (UGTs) inactivate and facilitate the excretion of estrogens to glucuronides (-G), the most abundant circulating estrogen conjugates. The identity of the conjugated estrogens formed by all known overexpressed UGTs (n = 16) was analyzed by comparison with retention time and mass fragmentation of authentic standards by HPLC tandem mass spectrometry methods. Six UGTs, namely 1A1, 1A3, 1A8, 1A9, 1A10, and 2B7, were found to glucuronidate estradiol (E2) and estrone (E1), their hydroxyls (OH), and their methoxy derivatives (MeO). Addition of glucuronic acid was catalyzed by specific UGTs at positions 2, 3, and 4 of the estrogens, whereas only E2 was conjugated at position 17 by UGT2B7. Kinetic parameters indicate that the conjugation of E2 at position 3 was predominantly catalyzed by 1A1, 1A3, and 1A8 and by 1A8 for E1. Conjugation of 2-OHE1/E2 and 2- and 4-MeOE1/E2 was selective at position 3, mostly catalyzed by 1A1 and 1A8. Of all UGTs, UGT2B7 demonstrated the highest catalytic activities for estrogens and at least 10- to 50-fold higher activity for the conjugation of genotoxic 4-hydroxycatecholestrogens at position 4, compared with the conjugation of E2, E1, and 2-hydroxycatecholestrogens. Its presence was further shown in the endometrium by RT-PCR and immunohistochemistry, localizing in the same cells expressing CYP1B1, involved locally in the formation of 4-hydroxycatecholestrogens. Data show that several UGT enzymes detected in the endometrium are involved in the glucuronidation of E2 and its 2-OH, 4-OH, and 2-MeO metabolites that exert various biological effects in the tissue.

  酸代谢。