3,17β-dibenzyloxy-11β-(3'-hydroxypropyl)estra-1,3,5(10)-triene | 147250-16-6

• 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
• 英文名称: 3,17β-dibenzyloxy-11β-(3'-hydroxypropyl)estra-1,3,5(10)-triene
• 英文别名: 3-(3,17β-bisbenzyloxyestra-1,3,5(10)-trien-11β-yl)propan-1-ol；3-[(8S,9S,11S,13S,14S,17S)-13-methyl-3,17-bis(phenylmethoxy)-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-11-yl]propan-1-ol
• CAS: 147250-16-6
• 化学式: C₃₅H₄₂O₃
• 分子量: 510.717
• InChiKey: XBGALXPZYQOUQG-RSYNKAAUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.5
• 重原子数：
  38
• 可旋转键数：
  9
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.49
• 拓扑面积：
  38.7
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3,17β-dibenzyloxy-11β-(3'-hydroxypropyl)estra-1,3,5(10)-triene 在 三氯化硼 、 potassium hydride 作用下， 以 二氯甲烷 、 甲苯 为溶剂， 反应 49.0h， 生成 11β-(3-ethoxypropyl)estra-1,3,5(10)-triene-3,17β-diol
  参考文献：
  名称：

  Nonpolar and Short Side Chain Groups at C-11β of Estradiol Result in Antiestrogens

  摘要：

  We have previously found that esters of 11beta-estradiol carboxylates are transformed from an estrogen into an antiestrogen when the 11beta-side chain is increased in length from four to five non-hydrogen atoms (n greater than or equal to 5). To understand the structural requirements for this transformation and obtain metabolically stable analogues that are not susceptible to esterase cleavage, we have synthesized other compounds having an 11beta-side chain composed of other functional groups: ketones, amides, ethers, and thiono esters. With the exception of amides, which bind poorly to the estrogen receptor (ER), all of these compounds exhibit antiestrogenic action when the side chain length is n greater than or equal to 5. Ethers (n greater than or equal to 5), studied in more detail, inhibit the action of estradiol with either ERalpha or ERbeta. In rat uteri they are estrogen antagonists/weak agonists and decrease the concentration of cholesterol in blood (an hepatic estrogenic action). Thus, these short chain and nonpolar 11beta-analogues of estradiol have tissue specific antiestrogenic/estrogenic actions, characteristics of selective estrogen receptor modulators.

  DOI：

  10.1021/jm049352x
• 作为产物：
  描述：

  雌二醇 在 三乙基硅烷 、 锂硼氢 、 三氟化硼乙醚 、 sodium hydride 、 pyridinium chlorochromate 、 2,3-二氯-5,6-二氰基-1,4-苯醌 、 儿萘酚硼烷 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 乙醚 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 70.17h， 生成 3,17β-dibenzyloxy-11β-(3'-hydroxypropyl)estra-1,3,5(10)-triene
  参考文献：
  名称：

  B，C和D环取代的雌二醇羧酸酯作为局部活性雌激素的合成和评估。

  摘要：

  我们合成了雌二醇的衍生物，这些衍生物经过结构修饰以用作“软”雌激素，并在人体的地理有限区域内发挥作用。没有全身作用的雌激素。我们以前已经显示了用16alpha取代的雌二醇类似物在类固醇环附近羧基化，既不与雌激素受体结合，也不激活雌激素反应性基因。但是，当羧酸被掩盖为酯时，它们会与受体结合并刺激雌激素反应。通过非特异性酯酶的酶促水解可以使这些雌激素失活，从而限制了它们的作用范围。在这里，我们描述了我们的持续研究，旨在通过在7α-，11β-，在甾体核中的15α-位和雌激素受体容纳大的取代基的位置。测试了这些化合物的雌激素受体结合（雌激素受体α和β），在培养的石川细胞中刺激雌激素敏感基因以及作为酶促水解的底物。在体内试验中测试了可能的候选药物的全身和局部雌激素作用。生物学研究表明，无论连接点如何，所有短链羧酸C-1至C-3均无激素作用，而许多酯则具有雌激素作用。类固醇核上的位点对激素活性和酯酶水

  DOI：

  10.1021/jm0204340

文献信息

• 11beta-short chain substituted estradiol analogs and their use in the treatment of menopausal symptoms and estrogen sensitive cancer
  申请人：YALE UNIVERSITY

  公开号：US20040142915A1

  公开（公告）日：2004-07-22

  The present invention relates to novel 11-&bgr; estradiol ester compounds and their use as locally active estrogens in the treatment of the symptomology of menopause and to treat estrogen sensitive cancers, including breast cancer.

  本发明涉及新型11-β雌二醇酯化合物及其作为局部活性雌激素在治疗更年期症状和治疗雌激素敏感性癌症，包括乳腺癌中的用途。
• Synthesis of 11β-ether-17α-ethinyl-3,17β-estradiols with strong ER antagonist activities
  作者：Jing-Xin Zhang、David C. Labaree、Richard B. Hochberg

  DOI：10.1016/j.cclet.2014.01.015

  日期：2014.4

  strong antagonists for preclinical development, we have synthesized other similar ER ligands with 11 β -ethers and with an additional ethinyl group at the 17 α -position in order to slow metabolism of the steroidal moiety. Here we report the synthesis and biological activity of two such compounds (11 β - i -PrO-propyl and 11 β - t -BuO-propyl ethers) with extremely strong antagonist activities.

  摘要我们以前发现，几种非极性的短链11β-醚和雌二醇的酯是选择性雌激素受体调节剂（SERMs）。出人意料的是，当11β-侧链的长度从4个非氢原子略微增加到5个非氢原子时，就会发生从有效雌激素到抗雌激素的转化。为了产生用于临床前开发的强拮抗剂，我们合成了其他相似的ER配体，这些配体具有11个β-醚和一个位于17α-位的附加乙炔基，以减慢甾体部分的新陈代谢。在这里，我们报告了两种具有极强拮抗剂活性的化合物（11β-i -PrO-丙基和11β-t -BuO-丙基醚）的合成和生物活性。
• Effect of Fluorination on the Pharmacological Profile of 11β Isomers of Fulvestrant in Breast Carcinoma Cells
  作者：Vangelis Agouridas、Emmanuel Magnier、Jean-Claude Blazejewski、Ioanna Laïos、Anny Cleeren、Denis Nonclercq、Guy Laurent、Guy Leclercq

  DOI：10.1021/jm801154q

  日期：2009.2.12

  We describe the synthesis of an 11 beta isomer 3 of the steroidal antiestrogen fulvestrant 2. Partial fluorination of the 11 beta side chain in 3 leads to 4, which still shows strong antiproliferative activity on MCF-7 cells. However, unlike 2 and 3, compound 4 fails to down-regulate estrogen receptor alpha (ER alpha). This result suggests that ER alpha down-regulation is not a sine qua non condition for the antitumor activity of steroidal antiestrogens.
• Nonpolar and Short Side Chain Groups at C-11β of Estradiol Result in Antiestrogens
  作者：Jing-xin Zhang、David C. Labaree、Richard B. Hochberg

  DOI：10.1021/jm049352x

  日期：2005.3.1

  We have previously found that esters of 11beta-estradiol carboxylates are transformed from an estrogen into an antiestrogen when the 11beta-side chain is increased in length from four to five non-hydrogen atoms (n greater than or equal to 5). To understand the structural requirements for this transformation and obtain metabolically stable analogues that are not susceptible to esterase cleavage, we have synthesized other compounds having an 11beta-side chain composed of other functional groups: ketones, amides, ethers, and thiono esters. With the exception of amides, which bind poorly to the estrogen receptor (ER), all of these compounds exhibit antiestrogenic action when the side chain length is n greater than or equal to 5. Ethers (n greater than or equal to 5), studied in more detail, inhibit the action of estradiol with either ERalpha or ERbeta. In rat uteri they are estrogen antagonists/weak agonists and decrease the concentration of cholesterol in blood (an hepatic estrogenic action). Thus, these short chain and nonpolar 11beta-analogues of estradiol have tissue specific antiestrogenic/estrogenic actions, characteristics of selective estrogen receptor modulators.
• Synthesis and Evaluation of B-, C-, and D-Ring-Substituted Estradiol Carboxylic Acid Esters as Locally Active Estrogens
  作者：David C. Labaree、Jing-xin Zhang、Heather A. Harris、Craig O'Connor、Toni Y. Reynolds、Richard B. Hochberg

  DOI：10.1021/jm0204340

  日期：2003.5.1

  great influence on hormonal activity and esterase hydrolysis. Formate esters at 7alpha and 15alpha were good estrogens, but lengthening the chain to acetate dramatically decreased hormonal activity. However, the 7alpha-formate esters were not enzymatically hydrolyzed. At 11beta, the acetate (methyl ester) was an effective estrogen, but increasing the chain length to propionate dramatically reduced hormonal

  我们合成了雌二醇的衍生物，这些衍生物经过结构修饰以用作“软”雌激素，并在人体的地理有限区域内发挥作用。没有全身作用的雌激素。我们以前已经显示了用16alpha取代的雌二醇类似物在类固醇环附近羧基化，既不与雌激素受体结合，也不激活雌激素反应性基因。但是，当羧酸被掩盖为酯时，它们会与受体结合并刺激雌激素反应。通过非特异性酯酶的酶促水解可以使这些雌激素失活，从而限制了它们的作用范围。在这里，我们描述了我们的持续研究，旨在通过在7α-，11β-，在甾体核中的15α-位和雌激素受体容纳大的取代基的位置。测试了这些化合物的雌激素受体结合（雌激素受体α和β），在培养的石川细胞中刺激雌激素敏感基因以及作为酶促水解的底物。在体内试验中测试了可能的候选药物的全身和局部雌激素作用。生物学研究表明，无论连接点如何，所有短链羧酸C-1至C-3均无激素作用，而许多酯则具有雌激素作用。类固醇核上的位点对激素活性和酯酶水