Tamoxifen butyl 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 butyl bromide
• 英文别名: butyl-[2-[4-[(Z)-1,2-diphenylbut-1-enyl]phenoxy]ethyl]-dimethylazanium;bromide
• 化学式: Br*C₃₀H₃₈NO
• 分子量: 508.542
• InChiKey: XHYMZYZWHWNTMN-DHKWPOFJSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  4.32
• 重原子数：
  33
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 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：

  正溴丁烷 、 他莫昔芬 反应 5.0h， 以94.8%的产率得到Tamoxifen butyl bromide
  参考文献：
  名称：

  Genomic action of permanently charged tamoxifen derivatives via estrogen receptor-α

  摘要：

  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.

  DOI：

  10.1016/j.bmc.2010.06.039

文献信息

• 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.