Tamoxifen ethyl bromide

• 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: Tamoxifen ethyl bromide
• 英文别名: ethyl bromide tamoxifen；2-[4-[(Z)-1,2-diphenylbut-1-enyl]phenoxy]ethyl-ethyl-dimethylazanium;bromide
• 化学式: Br*C₂₈H₃₄NO
• 分子量: 480.488
• InChiKey: BXPXDYCXXNBOQW-LXCLTORNSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  3.53
• 重原子数：
  31
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  9.2
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  溴乙烷 、 他莫昔芬 生成 Tamoxifen ethyl bromide
  参考文献：
  名称：

  Ethylbromide Tamoxifen, a Membrane-Impermeant Antiestrogen, Activates Smooth Muscle Calcium-Activated Large-Conductance Potassium Channels from the Extracellular Side

  摘要：

  他莫昔芬和 17-β-estradiol 可激活平滑肌钙激活大电导钾通道（BK 通道）。NPo（通道数量 N 乘以开放概率）的增加取决于调节性 β1 亚基的存在。此外，先前的一项研究表明，17-β-雌二醇可能与 β1 亚基上的一个细胞外位点结合。由于他莫昔芬和 17-β-estradiol 可能有一个共同的结合位点，我们假设他莫昔芬通过膜细胞外表面的一个位点激活 BK 通道。我们合成了一种他莫昔芬的膜渗透类似物--乙基溴化他莫昔芬，并在犬结肠平滑肌细胞的全细胞、外向型、细胞附着型和内向型斑块中测试了这一假设。乙溴他莫昔芬带正电荷，因此具有膜渗透性。在全细胞实验中，乙基溴化他莫昔芬增加了+40 mV正电位下的K+电流，这在以前被归因于BK通道。与他莫昔芬不同，乙基溴他莫昔芬不抑制延迟整流电流。在外侧贴片中，乙基溴他莫昔芬增加了 BK 通道的 NPo，其 EC50 值为 1 μM。乙基溴化他莫昔芬不会增加细胞附着或内向外贴片中的 BK 通道 NPo；但是，随后加入等摩尔他莫昔芬会增加 BK 通道 NPo。这两种药物都降低了 BK 通道的单位电导率，其程度与对 NPo 的影响相当，这表明它们与形成孔的α亚基有额外的相互作用。他莫昔芬与孔的相互作用得到了四乙基铵浓度-反应曲线右移的支持；类似的结果在伊比妥毒素和charybdotoxin阻滞中也很明显。我们的数据表明，乙基溴化他莫昔芬不易穿过质膜，而他莫昔芬与 BK 通道的结合是在细胞外部位。他莫昔芬的结合位点可能在 BK 通道 β1-亚基的细胞外环内，或者在一个尚未确定的具有细胞外结合位点的介质上。

  DOI：

  10.1124/mol.61.5.1105

文献信息

• Genomic action of permanently charged tamoxifen derivatives via estrogen receptor-α
  作者：Claudia Rivera-Guevara、Víctor Pérez-Alvarez、Rocío García-Becerra、David Ordaz-Rosado、Martha Sonia Morales-Ríos、Elizabeth Hernández-Gallegos、Austin J. Cooney、María Elena Bravo-Gómez、Fernando Larrea、Javier Camacho

  DOI：10.1016/j.bmc.2010.06.039

  日期：2010.8

  Tamoxifen is a selective estrogen receptor modulator widely used in oncology and reproductive endocrinology. In order to decrease its non-desirable effects and elucidate mechanisms of action, permanently charged tamoxifen derivatives (PCTDs) have been reported. Whether PCTDs have genomic effects remains controversial. Since the clinical relevance of tamoxifen, the necessity to have new anticancer drugs, and in order to gain insights into the mechanisms of action of PCTDs, we obtained six quaternary ammonium salts derived from tamoxifen including three new compounds. We characterized them by nuclear magnetic resonance, X-ray diffraction, electron microscopy, and/or high performance liquid chromatography, and detected them in cell lysates by liquid chromatography coupled to mass spectrometry. We evaluated their binding to estrogen receptor-alpha (ER alpha, their effect on the transcriptional activity mediated by ER alpha (gene reporter assays), and the proliferation of cancer cells (MCF-7 and cells from a cervical cancer primary culture). Structural studies demonstrated the expected identity of the molecules. All PCTDs did bind to ER alpha, one of them induced ER alpha-mediated transcription while two others inhibited such genomic action. Accordingly, PCTDs were detected in cell lysates. PCTDs inhibited cell proliferation, noteworthy, two of them displayed higher inhibition than tamoxifen. Structure-activity analysis suggests that PCTDs permanent positive charge and the length of the aliphatic chain might be associated to the biological responses studied. We suggest genomic effects as a mechanism of action of PCTDs. The experimental approaches here used could lead to a better design of new therapeutic molecules and help to elucidate molecular mechanisms of new anticancer drugs. (C) 2010 Elsevier Ltd. All rights reserved.
• Functional inhibition of intestinal and uterine muscles by non-permeant triphenylethylene derivatives
  作者：Jorge Marrero-Alonso、Benito García Marrero、Tomás Gómez、Mario Díaz

  DOI：10.1016/j.ejphar.2005.11.031

  日期：2006.2

  We have previously shown that the triphenylethylene antiestrogen tamoxifen reversibly inhibited spontaneous contractile activity in isolated duodenal muscle. Now, we have synthesized different quaternary ammonium salts of tamoxifen by changing the substituents oil the nitrogen of the alkylaminoethoxy side-chain, to obtain plasma membrane impermeable compounds. Synthesized molecules were N-desmethyl-tamoxifen-hydrochloride, ethylbromide-tamoxifen and butylbromide-tamoxifen, which differed in the size of their ionic side-chain. All compounds rapidly and reversibly inhibited spontaneous and CaCl2-induced contractions in mouse duodenum and uterus. Dose-response analyses revealed a structure-activity relationship where the larger the side-chain the higher the inhibitory potency. Fourier analyses on triphenylethylene-relaxed duodenal tissues showed that harmonic components of contractile activity were readily recovered upon exposure to the L-type calcium channel agonist 1,4-dihydro-2,6-dimethyl-5-nitro-4-[2-(trifluoromethyl)phenyl]-pyridine-3-carboxilic acid methyl ester (BAY-K644). Likewise, BAY-K644 completely reversed tripluenylethylene-induced effects oil uterine tonic tension. Our experiments suggest that impermeant tamoxifen derivatives relax visceral smooth Muscle through a membrane-mediated non-genomic mechanism that involves inhibition of L-type calcium channels. (c) 2005 Elsevier B.V. All rights reserved.