4-(1-(4-(2-chloroethoxy)phenyl)-2-phenylbut-1-en-1-yl)phenol

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: 4-(1-(4-(2-chloroethoxy)phenyl)-2-phenylbut-1-en-1-yl)phenol
• 英文别名: 4-[1-[4-(2-Chloroethoxy)phenyl]-2-phenylbut-1-enyl]phenol
• 化学式: C₂₄H₂₃ClO₂
• 分子量: 378.898
• InChiKey: QDLAEGCSWYNGSD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.3
• 重原子数：
  27
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  29.5
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-(1-(4-(2-chloroethoxy)phenyl)-2-phenylbut-1-en-1-yl)phenol 在 phase transfer catalyst sodium methylate 作用下， 反应 22.0h， 生成 4-羟基三苯氧胺
  参考文献：
  名称：

  McCague, Raymond, Journal of Chemical Research, Miniprint, 1986, # 2, p. 771 - 793

  摘要：

  DOI：
• 作为产物：
  描述：

  2-苯基丁酸 在 盐酸 、 aluminum (III) chloride 、 氯化亚砜 作用下， 以 甲醇 、 乙醚 、 二氯甲烷 为溶剂， 生成 4-(1-(4-(2-chloroethoxy)phenyl)-2-phenylbut-1-en-1-yl)phenol
  参考文献：
  名称：

  Design and synthesis of tamoxifen derivatives as a selective estrogen receptor down-regulator

  摘要：

  We designed and synthesized an estrogen receptor (ER) down-regulator (5), which is a derivative of tamoxifen with a long alkyl side chain. Compound 5 effectively reduced ER protein levels in MCF-7 cells and had an antagonistic effect. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.11.078

文献信息

• Molecular design, chemical synthesis, and biological evaluation of agents that selectively photo-degrade the transcription factor estrogen receptor-α
  作者：Kana Tsumura、Akane Suzuki、Takeo Tsuzuki、Shuho Tanimoto、Hajime Kaneko、Shuichi Matsumura、Masaya Imoto、Kazuo Umezawa、Daisuke Takahashi、Kazunobu Toshima

  DOI：10.1039/c1ob05629h

  日期：——

  2-Phenylquinoline (1) degraded proteins under photo-irradiation with long-wavelength UV light without additives and under neutral conditions. We designed and synthesized a 2-phenylquinoline-estrogen receptor-α (ER-α) agonist (hybrid 2) and a 2-phenylquinoline-ER-α antagonist (hybrid 3) containing estradiol and 4-hydroxytamoxifen moieties, respectively. These 2-phenylquinoline hybrids effectively and selectively

  2-苯基喹啉（1）在无添加剂的长波长紫外光和中性条件下，在光辐照下降解了蛋白质。我们设计并合成了分别含有雌二醇和4-羟基他莫昔芬部分的2-苯基喹啉-雌激素受体-α（ER-α）激动剂（杂交2）和2-苯基喹啉-ER-α拮抗剂（杂交3）。这些2-苯基喹啉杂种有效地和选择性地光降解了目标转录因子ER-α，后者对雌二醇和4-羟基他莫昔芬具有很高的亲和力。在玻璃容器和MCF-7乳腺癌细胞中均检测了靶标选择性光降解，这取决于ER-α的生长。另外，2-苯基喹啉-雌二醇杂化物2在没有光照射的情况下，它起着ER-α激动剂的作用，促进了MCF-7的生长，而由于ER-α的光降解，它在光照射后抑制了MCF-7细胞的生长。相反，由于4-羟基他莫昔芬部分对ER-α的拮抗作用，在没有光照射的情况下，2-苯基喹啉-4-羟基他莫昔芬杂种3抑制MCF-7细胞的生长，并且在光辐照后显着抑制细胞4-羟基他莫昔芬部分的双重拮抗作用和ER-α的光降解引起细胞生长。
• Tamoxifen and Fulvestrant Hybrids Showed Potency as Selective Estrogen Receptor Down-Regulators
  作者：Takuji Shoda、Masashi Kato、Takuma Fujisato、Yosuke Demizu、Hideshi Inoue、Mikihiko Naito、Masaaki Kurihara

  DOI：10.2174/1573406412666160805101408

  日期：2017.4.10

  Background: Estrogen receptors (ERs) are an important target for the management of breast cancers. Selective estrogen receptor down-regulators (SERDs) block ER activity, as well as reduce ERα protein levels in cells, and therefore are promising therapeutic agents for the treatment of breast cancers. Objective: In order to develop potent SERDs, we prepared tamoxifen and fulvestrant hybrids and evaluated their binding activity and down-regulation of ERα. Methods: We designed and synthesized tamoxifen derivatives, which had a 4,4,5,5,5- pentafluoropentyl group on the terminal alkyl chain. The oxidation state of the sulfur atom and alkyl length between the sulfur and nitrogen atoms were varied. Western blotting was performed to determine the ability to down-regulate ERα. Binding affinities of synthesized compounds were evaluated by a fluorescence polarization-based competitive binding assay. Results: We successfully prepared nine compounds. Treatment with 11, 14, and 17 effectively reduced ERα protein levels in MCF-7 cells in a concentration-dependent manner. This reduction was inhibited by a proteasome inhibitor. The ability of 14 to down-regulate the ERα protein level was equal to fulvestrant. All compounds showed a largely equal affinity for ERα. Conclusion: As indicated by Western blots, the ERα degradation activity was observed only in the series of butyl linker derivatives, namely, 11, 14, and 17. These findings suggest that the specific length of the alkyl chain is an important factor in controlling the down-regulation of ER. These results provide useful information for designing promising SERD candidates.

  背景：雌激素受体（ER）是治疗乳腺癌的重要靶点：雌激素受体（ER）是治疗乳腺癌的重要靶点。选择性雌激素受体下调剂（SERDs）能阻断ER的活性，降低细胞中ERα蛋白的水平，因此是治疗乳腺癌很有前景的治疗药物。 目的：为了开发强效的SERDs，我们制备了他莫昔芬和氟维司群混合物，并评估了它们的结合力和下调作用：为了开发强效的 SERDs，我们制备了他莫昔芬和氟维司群混合物，并评估了它们的结合活性和对 ERα 的下调作用。 方法：我们设计并合成了他莫昔芬和氟维司群混合物：我们设计并合成了他莫昔芬衍生物，这些衍生物的末端烷基链上含有4,4,5,5,5-五氟戊基。硫原子的氧化状态以及硫原子和氮原子之间的烷基长度各不相同。通过 Western 印迹法测定其下调 ERα 的能力。通过基于荧光偏振的竞争性结合试验评估了合成化合物的结合亲和力。 结果：我们成功制备了九种化合物。用 11、14 和 17 处理 MCF-7 细胞，能以浓度依赖性方式有效降低 ERα 蛋白水平。蛋白酶体抑制剂抑制了这种降低作用。14 下调 ERα 蛋白水平的能力与氟维司群相当。所有化合物对ERα的亲和力基本相同。 结论：正如 Western 印迹所示，只有丁基连接体衍生物系列（即 11、14 和 17）具有降解 ERα 的活性。这些发现表明，烷基链的特定长度是控制ER下调的一个重要因素。这些结果为设计有前途的 SERD 候选物提供了有用的信息。
• High Affinity Fluorescent Ligands for the Estrogen Receptor
  作者：Frank Abendroth、Marthe Solleder、Dorothea Mangoldt、Pia Welker、Kai Licha、Marcus Weber、Oliver Seitz

  DOI：10.1002/ejoc.201403489

  日期：2015.4

  Fluorescent binders of the estrogen receptor (ER) are used in binding assays and in detection or imaging studies. However, fluorescence labelling of ER ligands usually leads to substantial decreases in binding affinity. In this study, we describe the development of high affinity fluorescent ER ligands. Cyanine dyes of the MiDye series were directly attached to the SERMs 4-hydroxytamoxifen (OHT) and

  雌激素受体 (ER) 的荧光结合剂用于结合测定和检测或成像研究。然而，ER 配体的荧光标记通常会导致结合亲和力的显着降低。在这项研究中，我们描述了高亲和力荧光 ER 配体的发展。MiDye 系列的花青染料直接连接到 SERM 4-羟基三苯氧胺 (OHT) 和雷洛昔芬 (Ral) 上；链接器被故意省略。这种方法产生的结合物具有优于天然配体雌二醇的 ERα 结合亲和力。在 600–800 nm 范围内发射的 OHT-和 Ral-MiDye 偶联物。第一轮染色实验表明，偶联物在表达雌激素结合受体的细胞中积累，而不是单独的染料。
• Design and Synthesis of Norendoxifen Analogues with Dual Aromatase Inhibitory and Estrogen Receptor Modulatory Activities
  作者：Wei Lv、Jinzhong Liu、Todd C. Skaar、David A. Flockhart、Mark Cushman

  DOI：10.1021/jm501218e

  日期：2015.3.26

  Both selective estrogen receptor modulators and aromatase inhibitors are widely used for the treatment of breast cancer. Compounds with both aromatase inhibitory and estrogen receptor modulatory activities could have special advantages for treatment of breast cancer. Our previous efforts led to the discovery of norendoxifen as the first compound with dual aromatase inhibitory and estrogen receptor binding activities. To optimize its efficacy and aromatase selectivity versus other cytochrome P450 enzyme, a series of structurally related norendoxifen analogues were designed and synthesized. The most potent compound, 4'-hydroxynorendoxifen (10), displayed elevated inhibitory potency against aromatase and enhanced affinity for estrogen receptors when compared to norendoxifen. The selectivity of 10 for aromatase versus other cytochrome P450 eniymes was also superior to norendoxifen. 4'-Hydroxynorendoxifen is therefore an interesting lead for further development to obtain new anticancer agents of potential value for the treatment of breast cancer.
• Synthesis and evaluation of tamoxifen derivatives with a long alkyl side chain as selective estrogen receptor down-regulators
  作者：Takuji Shoda、Masashi Kato、Rintaro Harada、Takuma Fujisato、Keiichiro Okuhira、Yosuke Demizu、Hideshi Inoue、Mikihiko Naito、Masaaki Kurihara

  DOI：10.1016/j.bmc.2015.05.002

  日期：2015.7

  Estrogen receptors (ERs) play a major role in the growth of human breast cancer cells. An antagonist that acts as not only an inhibitor of ligand binding but also an inducer of the down-regulation of ER would be useful for the treatment for ER-positive breast cancer. We previously reported the design and synthesis of a selective estrogen receptor down-regulator (SERD), (E/Z)-4-(1-4-[2-(dodecylamino) ethoxy] phenyl}-2-phenylbut-1-en-1-yl) phenol (C12), which is a tamoxifen derivative having a long alkyl chain on the amine moiety. This compound induced degradation of ER alpha via a proteasome-dependent pathway and showed an antagonistic effect in MCF-7 cells. With the aim of increasing the potency of SERDs, we designed and synthesized various tamoxifen derivatives that have various lengths and terminal groups of the long alkyl side chain. During the course of our investigation, C10F having a 10-fluorodecyl group on the amine moiety of 4-OHT was shown to be the most potent compound among the tamoxifen derivatives. Moreover, computational docking analysis suggested that the long alkyl chain interacted with the hydrophobic region on the surface of the ER, which is a binding site of helix 12 and coactivator. These results provide useful information to develop promising candidates as SERDs. (C) 2015 Elsevier Ltd. All rights reserved.