α-hydroxytamoxifen | 97151-02-5

• 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: α-hydroxytamoxifen
• 英文别名: (E)-(+)-alpha-Hydroxytamoxifen；alpha-Hydroxytamoxifen；(E)-4-[4-[2-(dimethylamino)ethoxy]phenyl]-3,4-diphenylbut-3-en-2-ol
• CAS: 97151-02-5
• 化学式: C₂₆H₂₉NO₂
• 分子量: 387.522
• InChiKey: BPHFBQJMFWCHGH-QPLCGJKRSA-N

物化性质

• 熔点：
  115-119°C
• 沸点：
  533.8±50.0 °C(Predicted)
• 密度：
  1.094±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  29
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  32.7
• 氢给体数：
  1
• 氢受体数：
  3

ADMET

代谢

Alpha-羟基他莫昔芬是他莫昔芬的一个已知人体代谢物。

Alpha-Hydroxytamoxifen is a known human metabolite of tamoxifen.

来源:NORMAN Suspect List Exchange

安全信息

• 海关编码：
  2922509090

制备方法与用途

生物活性方面，α-羟基他莫昔芬是他莫昔芬的代谢产物，在缺乏代谢酶的情况下能够与DNA相互作用，从而导致DNA加合物的形成。

反应信息

• 作为反应物：
  描述：

  α-hydroxytamoxifen 在 palladium on activated charcoal 吡啶 、 氢氧化钾 、 Tris-HCl buffer 、 氢气 、 一水合肼 、 三乙胺 作用下， 以 甲醇 、 乙二醇 、 乙酸乙酯 、 乙腈 、 苯 为溶剂， 反应 41.0h， 生成 trans-α-(N²-Deoxyguanosinyl)-N-desmethyltamoxifen
  参考文献：
  名称：

  Identification of Tamoxifen−DNA Adducts Induced by α-Acetoxy-N-desmethyltamoxifen

  摘要：

  Treatment with tamoxifen increased the risk of endometrial cancers in breast cancer patients and women participating in the chemoprevention study. In our laboratory, tamoxifen-DNA adducts, including alpha-(N-2-deoxyguanosinyl)tamoxifen (dG-N-2-TAM), were detected in the endometrium of women taking tamoxifen [Shibutani, S., et al. (1999) Chem. Res. Toxicol. 12, 646-653]. On the basis of recent animal studies, deoxyguanosinyl-N-desmethyltamoxifen (dG-N-desmethylTAM) adducts are also suspected to be formed in the liver. In the study presented here, we synthesized alpha-acetoxy-N-desmethyltamoxifen as a model activated metabolite of N-desmethyltamoxifen. The overall yield of alpha-acetoxy-N-desmethyltamoxifen from alpha-hydroxytamoxifen was approximately 42%. alpha-Acetoxy-N-desmethyltamoxifen was highly reactive to 2'-deoxyguanosine, as was similarly observed for tamoxifen alpha-sulfate. The two reaction products were identified as a mixture of epimers of the trans form or cis form of alpha-(N-2-deoxyguanosinyl)N-desmethyltamoxifen (dG-N-2-N-desmethylTAM) by mass and proton magnetic resonance spectres copy. In addition, the trans and cis forms of dG 3'-monophosphate-N-2-N-desmethylTAM were prepared as standard markers for P-32-postlabeling/HPLC analysis. Using this technique, dG-N-2-N-desmethylTAM adducts were detected in calf thymus DNA reacted with alpha-acetoxy-N-desmethyltamoxifen.

  DOI：

  10.1021/tx000074o
• 作为产物：
  描述：

  2-硝基-3-(4-甲氧基苯基)丙酸乙酯 在 正丁基锂 、 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 0.67h， 生成 α-hydroxytamoxifen
  参考文献：
  名称：

  他莫昔芬的羟基衍生物。

  摘要：

  在探索影响他莫昔芬[反-（Z）-1- [4- [2-（二甲基氨基）乙氧基] RBA（相对于雌二醇的大鼠子宫雌激素受体的结合亲和力）的结构特征苯基] -1,2，2-二苯基-1-丁烯]系列，已经合成了在1-苯基上被各种取代的几种衍生物。[在他莫昔芬系列中，定义几何异构体的构型并取决于芳族部分和乙基中取代基的位置和性质的描述符E和Z可能会有所变化，尽管相对构型（顺式或反式）才不是。为了避免混淆，在本文中将使用术语顺式和反式来表示4- [2-（二甲基氨基）乙氧基]苯基与乙基（或羟乙基，羟丙基，每一合成的最后阶段涉及叔醇的酸催化脱水，与已知的近似等摩尔顺式的3-和4-羟基衍生物相反，反式混合物，仅获得2-羟基，2-甲基，2，4-二羟基和4-羟基-2-甲基衍生物的反式形式。同样，与3-和4-羟基衍生物的反式形式很容易平衡成顺式，反式混合物相反，反式2-羟基衍生物不能被异构化。他莫昔芬和2-甲基他莫昔芬

  DOI：

  10.1021/jm00148a020

文献信息

• Method for the treatment or prevention of lower urinary tract symptoms
  申请人：——

  公开号：US20040248989A1

  公开（公告）日：2004-12-09

  This invention concerns a method for treatment or prevention of lower urinary tract symptoms with or without pelvic pain in an individual, said method comprising administering to the individual an effective amount of a selective estrogen receptor modulator, or an isomer, isomer mixture or a pharmaceutically acceptable salt thereof.

  这项发明涉及一种用于治疗或预防个体下尿道症状的方法，该方法包括向个体投予有效量的选择性雌激素受体调节剂，或其异构体、异构体混合物或药用可接受的盐。
• Photoredox-Catalyzed C–H Arylation of Internal Alkenes to Tetrasubstituted Alkenes: Synthesis of Tamoxifen
  作者：Quannan Wang、Xiaoge Yang、Ping Wu、Zhengkun Yu

  DOI：10.1021/acs.orglett.7b03223

  日期：2017.11.17

  Visible-light-induced direct C–H arylation of S,S-functionalized internal alkenes, that is, α-oxo ketene dithioacetals and analogues, has been efficiently realized with aryldiazonium salts (ArN2BF4) as coupling partners and Ru(bpy)3Cl2·6H2O as photosensitizer at ambient temperature. The strategy to activate the internal olefinic C–H bond by both the alkylthio and electron-withdrawing functional groups

  可见光诱导的直接C-H芳基化S，S -官能化的烯烃的内部，即，α氧代烯酮二硫和类似物，已经有效地与芳基重氮盐（ARN实现2 BF 4）作为偶联和Ru（联吡啶）3 Cl 2 ·6H 2 O在环境温度下作为光敏剂。研究了通过烷硫基和吸电子官能团激活内部烯烃CH键的策略。该合成方案已成功应用于包括他莫昔芬在内的全碳四取代烯烃的合成。
• [EN] ANTIESTROGENS FOR BREAST CANCER THERAPY<br/>[FR] ANTI-ESTROGÈNES POUR THÉRAPIE DU CANCER DU SEIN
  申请人：UNIV NEW YORK STATE RES FOUND

  公开号：WO2010107474A1

  公开（公告）日：2010-09-23

  This invention provides a compound having the structure wherein α, q, X, and R1-R14 are defined herein, or a salt thereof. This invention also provides a process for preparing the above compound, a pharmaceutical composition comprising the above compound, and a method of inhibiting tumor proliferation in a mammal.

  该发明提供了一种具有结构的化合物，其中α、q、X和R1-R14在此处定义，或其盐。该发明还提供了制备上述化合物的方法，包括上述化合物的药物组合物，以及在哺乳动物体内抑制肿瘤增殖的方法。
• The tamoxifen cation reacts to give indene products
  作者：Cristina Sanchez、Robert A McClelland

  DOI：10.1139/v00-122

  日期：2000.9.1

  The tamoxifen carbocation (Ph(Ar)C=CPh-CH⁺-CH₃, Ar = 4-Me₂NCH₂CH₂OC₆H₄) is generated from acetate and sulfate precursors by S_N1 ionization in water. The cation exists in (E) and (Z) forms which equilibrate before reaction. The major products are the α-hydroxytamoxifens Ph(Ar)C=CPh-CHOH-CH₃, both (E) 64% and (Z) 29%, with the ratio independent of the configuration of the starting ester. Two minor products with a total yield of 7% account for the rest of the products. These have been characterized as indenes derived from intramolecular cyclization, a 4.5% yield of the indene derived from cyclization into the Ar ring with 2.5% due to cyclization into the phenyl ring. Experiments in acid solutions (0.01-0.1 M HCl) starting with pure (E)- or (Z)-α-hydroxytamoxifen reveal that the two alcohols equilibrate. This occurs by H⁺-catalyzed formation of the carbocation followed by water capture. Occurring about 10-fold slower than this isomerization is an irreversible process resulting in the two indenes. This cyclization will result in the destruction of the α-hydroxytamoxifens upon exposure to acidic conditions and also makes the direct observation of the tamoxifen carbocation under super-acid conditions difficult, if not impossible. The indenes do form in low yield whenever the tamoxifen carbocation is generated from an S_N1 precursor. Thus these products could serve as markers for the formation of the tamoxifen carbocation in cellular systems or in in vivo experiments.Key words: carbocation, indene, allylic cation, isomerization.

  他莫昔芬卡阳离子（Ph（Ar）C=CPh-CH⁺-CH₃，Ar = 4-Me₂NCH₂CH₂OC₆H₄）是由乙酸盐和硫酸盐前体在水中通过S_N1电离生成的。这个阳离子存在（E）和（Z）形式，在反应前平衡。主要产物是α-羟基他莫昔芬Ph（Ar）C=CPh-CHOH-CH₃，分别为（E）64%和（Z）29%，比例与起始酯的构型无关。两种产物的总产率为7%，其余的产品为两种次要产物。这些次要产物已被确定为由分子内环化衍生的茚烯，其中4.5%的产率来自于环化成Ar环的茚烯，2.5%来自于环化成苯环的茚烯。在酸性溶液（0.01-0.1 M HCl）中进行的实验，从纯（E）或（Z）-α-羟基他莫昔芬开始，显示这两种醇会平衡。这是通过H⁺催化形成卡阳离子，然后被水捕获来实现的。比这种异构化慢大约10倍的是一个不可逆过程，导致两种茚烯的形成。这种环化将导致α-羟基他莫昔芬在酸性条件下暴露时被破坏，并且使在超酸条件下直接观察他莫昔芬卡阳离子变得困难，甚至不可能。每当他莫昔芬卡阳离子由S_N1前体生成时，茚烯都会以低产率形成。因此，这些产物可以作为细胞系统或体内实验中他莫昔芬卡阳离子形成的标志。关键词：卡阳离子，茚烯，烯丙基阳离子，异构化。
• Preparation of Oligodeoxynucleotides Containing a Diastereoisomer of α-(<i>N</i>²-2‘-Deoxyguanosinyl)tamoxifen by Phosphoramidite Chemical Synthesis
  作者：Y. R. Santosh Laxmi、Naomi Suzuki、Lakkaraju Dasaradhi、Francis Johnson、Shinya Shibutani

  DOI：10.1021/tx0101494

  日期：2002.2.1

  diastereoisomers of trans- and cis-forms of alpha-(N(2)-deoxyguanosinyl)tamoxifen (dG-N(2)-TAM) and alpha-(N(2)-deoxyguanosinyl)-N-desmethyltamoxifen. In the study presented here, we prepared oligodeoxynucleotides containing a diastereoisomer of dG-N(2)-TAM by phosphoramidite chemical synthesis. Initially, the trans- and cis-forms of alpha-aminotamoxifen (alpha-NH(2)-TAM) were synthesized from alpha-hydroxytamoxifen

  用他莫昔芬抗雌激素（TAM）治疗用于内分泌治疗或预防乳腺癌的妇女患子宫内膜癌的风险增加。在用TAM处理过的啮齿动物的肝脏中和服用TAM的妇女的子宫内膜中均检测到TAM-DNA加合物。主要的TAM加合物已被确定为α-（N（2）-脱氧鸟苷基）他莫昔芬（dG-N（2）-TAM）和α-（N（2）-脱氧鸟苷）-的反式和顺式非对映异构体- N-去甲基他莫昔芬。在这里介绍的研究中，我们通过亚磷酰胺化学合成制备了含有dG-N（2）-TAM非对映异构体的寡脱氧核苷酸。最初，使用Mitsunobu反应从α-羟基他莫昔芬合成反式和顺式形式的α-氨基他莫昔芬（α-NH（2）-TAM），然后进行水解。之后，通过将反式和顺式形式的α-NH（2）-TAM与2-氟-（O（6）-2-（三甲基甲硅烷基）乙基）-2'-脱氧肌苷的DMT衍生物偶联，分别以高收率制备了DMT-dG-N（2）-TAM的-和顺式形式，并用于制备亚磷酰胺