4-(1-(4-(2-(dimethylamino)ethoxy)phenyl)-2-phenylprop-1-en-1-yl)phenylbutyrate

• 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-(dimethylamino)ethoxy)phenyl)-2-phenylprop-1-en-1-yl)phenylbutyrate
• 化学式: C₂₉H₃₃NO₃
• 分子量: 443.586
• InChiKey: VOQJVTVQBYNZTP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.31
• 重原子数：
  33.0
• 可旋转键数：
  10.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  38.77
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为产物：
  描述：

  4,4'-二羟基二苯甲酮 在 四氯化钛 、 potassium carbonate 、 三乙胺 、 锌 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 18.5h， 生成 4-(1-(4-(2-(dimethylamino)ethoxy)phenyl)-2-phenylprop-1-en-1-yl)phenylbutyrate
  参考文献：
  名称：

  Design and synthesis of novel tamoxifen analogues that avoid CYP2D6 metabolism

  摘要：

  Tamoxifen (TAM) is a widely used drug in the prophylaxis and treatment of breast cancer. TAM is metabolized to the more active 4-hydroxytamoxifen (4-OH-TAM) and endoxifen by cytochrome P450 (CYP) mainly CYP2D6 and CYP3A4 enzymes. Due to the genetic polymorphisms in CYP2D6 genes, high variation in the clinical outcomes of TAM treatment is observed among women of different populations. To address this issue, novel TAM analogues with possible altered activation pathways were synthesized. These analogues were tested for their antiproliferative action on MCF-7 breast cancer cell lines as well as their binding affinity for estrogen receptor (ER) ER-alpha and ER-beta receptors. These entire novel compounds showed better antiproliferative activity than did TAM on the MCF-7 cells. Moreover, compound 10 exhibited a half maximal growth inhibition (GI(50)) that was 1000 times more potent than that of TAM (GI(50) < 0.005 mu M vs 1.58 mu M, respectively). Along with a broad spectrum activity on various cancer cell lines, all the TAM analogues showed considerable activity on the ER-negative breast cancer cell line. For further study, compound 10 was incubated in human liver microsomes (HLM), human hepatocytes (hHEP) and CYP2D6 supersomes. The active hydroxyl metabolite was detected after incubation in HLM and hHEP, implicating the involvement of other enzymes in its metabolism. These results prove that this novel series of TAM analogues might provide improved clinical outcomes for poor 2D6 metabolizers. (C) 2016 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2016.02.026

文献信息

• Design and synthesis of novel tamoxifen analogues that avoid CYP2D6 metabolism
  作者：Nermin S. Ahmed、Nehal H. Elghazawy、Ahmed K. ElHady、Matthias Engel、Rolf W. Hartmann、Ashraf H. Abadi

  DOI：10.1016/j.ejmech.2016.02.026

  日期：2016.4

  Tamoxifen (TAM) is a widely used drug in the prophylaxis and treatment of breast cancer. TAM is metabolized to the more active 4-hydroxytamoxifen (4-OH-TAM) and endoxifen by cytochrome P450 (CYP) mainly CYP2D6 and CYP3A4 enzymes. Due to the genetic polymorphisms in CYP2D6 genes, high variation in the clinical outcomes of TAM treatment is observed among women of different populations. To address this issue, novel TAM analogues with possible altered activation pathways were synthesized. These analogues were tested for their antiproliferative action on MCF-7 breast cancer cell lines as well as their binding affinity for estrogen receptor (ER) ER-alpha and ER-beta receptors. These entire novel compounds showed better antiproliferative activity than did TAM on the MCF-7 cells. Moreover, compound 10 exhibited a half maximal growth inhibition (GI(50)) that was 1000 times more potent than that of TAM (GI(50) < 0.005 mu M vs 1.58 mu M, respectively). Along with a broad spectrum activity on various cancer cell lines, all the TAM analogues showed considerable activity on the ER-negative breast cancer cell line. For further study, compound 10 was incubated in human liver microsomes (HLM), human hepatocytes (hHEP) and CYP2D6 supersomes. The active hydroxyl metabolite was detected after incubation in HLM and hHEP, implicating the involvement of other enzymes in its metabolism. These results prove that this novel series of TAM analogues might provide improved clinical outcomes for poor 2D6 metabolizers. (C) 2016 Elsevier Masson SAS. All rights reserved.