N-去甲基(E)-alpha-羟基他莫昔芬 | 162070-61-3

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 中文名称: N-去甲基(E)-alpha-羟基他莫昔芬
• 英文名称: alpha-Hydroxy-N-desmethyltamoxifen
• 英文别名: (E)-4-[4-(2-Methylaminoethoxy)phenyl]-3,4-diphenylbut-3-en-2-ol；(E)-α-Hydroxy-N-desmethyltamoxifen；(E)-4-[4-[2-(methylamino)ethoxy]phenyl]-3,4-diphenylbut-3-en-2-ol
• CAS: 162070-61-3
• 化学式: C₂₅H₂₇NO₂
• 分子量: 373.495
• InChiKey: GREXPZNIZPCGIV-IZHYLOQSSA-N

物化性质

• 熔点：
  >50oC (dec.)
• 沸点：
  539.9±50.0 °C(Predicted)
• 密度：
  1.101±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于DMSO（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  28
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  41.5
• 氢给体数：
  2
• 氢受体数：
  3

ADMET

代谢

Alpha-羟基-N-去甲基他莫昔芬是N-去甲基他莫昔芬的人类已知代谢物。

Alpha-hydroxy-N-desmethyltamoxifen is a known human metabolite of N-Desmethyltamoxifen.

来源:NORMAN Suspect List Exchange

反应信息

• 作为反应物：
  描述：

  N-去甲基(E)-alpha-羟基他莫昔芬 在 palladium on activated charcoal 吡啶 、 氢气 、 三乙胺 作用下， 以 甲醇 、 乙酸乙酯 为溶剂， 反应 18.0h， 生成 α-Acetoxy-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：

  (E)-4-{4-[2-(N-Ethoxycarbonyl-N-methylamino)ethoxy]phenyl}-3,4-diphenyl-3-buten-2-ol 在 氢氧化钾 、 一水合肼 作用下， 以 乙二醇 为溶剂， 反应 2.0h， 生成 N-去甲基(E)-alpha-羟基他莫昔芬
  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

文献信息

• Characterization of the Major DNA Adduct Formed by α-Hydroxy-<i>N</i>-desmethyltamoxifen in Vitro and in Vivo
  作者：Gonçalo Gamboa da Costa、L. Patrice Hamilton、Frederick A. Beland、M. Matilde Marques

  DOI：10.1021/tx990187b

  日期：2000.3.1

  cancer in women. Recent reports suggest that it may be genotoxic in humans. N-Desmethyltamoxifen is a major tamoxifen metabolite that has been proposed to be responsible for one of the major adducts detected in liver DNA of rats treated with tamoxifen. The metabolic activation of N-desmethyltamoxifen to DNA binding products may involve oxidation to alpha-hydroxy-N-desmethyltamoxifen followed by esterification

  他莫昔芬在大鼠中具有肝癌作用，并且与女性子宫内膜癌的风险增加有关。最近的报道表明它可能对人类有遗传毒性。N-去甲基他莫昔芬是一种主要的他莫昔芬代谢产物，已被认为是他莫昔芬治疗大鼠肝脏DNA中检测到的主要加合物之一。N-去甲基他莫昔芬对DNA结合产物的代谢活化可能涉及氧化成α-羟基-N-去甲基他莫昔芬，然后进行酯化。在这里提出的研究中，我们报告了α-羟基-N-去甲基他莫昔芬的合成以及从α-亚砜氧基-N-去甲基他莫昔芬体外获得的主要加合物的表征为（E）-α-（deoxyguanosin-N（2） -基）-N-去甲基他莫昔芬。此外，我们将（32）P后标记与HPLC结合使用，比较了用他莫昔芬或等摩尔剂量的α-羟基-N-去甲基他莫昔芬强饲法治疗的雌性Sprague-Dawley大鼠肝脏中形成的加合物。我们得出的结论是，体内形成的一种主要加合物，以前曾建议衍生自N-去甲基他莫昔芬，在色谱上与α-（脱氧
• Synthesis of oligodeoxynucleotides containing a single diastereoisomer of α-(N2-2′-deoxyguanosinyl)-N-desmethyltamoxifen
  作者：Y.R Santosh Laxmi、Naomi Suzuki、Sung Yeon Kim、Shinya Shibutani

  DOI：10.1016/j.bmcl.2004.05.030

  日期：2004.8

  A phosphoramidite chemical synthesis of oligodeoxynucleotides containing a diastereoisomer of (E)-alpha-(N-2-deoxyguanosinyl)-N-desmethyltamoxifen, a major tamoxifen (TAM)-derived DNA adduct in animal and women treated with TAM, was described. The site-specifically modified oligodeoxynucleotide can be used for mutagenesis, DNA repair, and 3D structural studies and also as standard for quantitative analysis of TAM-DNA adducts in animal and human. (C) 2004 Elsevier Ltd. All rights reserved.