4-(2-chlorophenethyl)morpholine | 1157077-96-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 4-(2-chlorophenethyl)morpholine
• 英文别名: 4-[2-(2-chlorophenyl)ethyl]morpholine
• CAS: 1157077-96-7
• 化学式: C₁₂H₁₆ClNO
• 分子量: 225.718
• InChiKey: WZUNKGDZXCQIQT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  15
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  12.5
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  吗啉 、 2-氯苯乙基溴 在 potassium carbonate 作用下， 以 乙腈 为溶剂， 以58%的产率得到4-(2-chlorophenethyl)morpholine
  参考文献：
  名称：

  Benzylmorpholine Analogs as Selective Inhibitors of Lung Cytochrome P450 2A13 for the Chemoprevention of Lung Cancer in Tobacco Users

  摘要：

  4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮（NNK）是烟草中最常见的致癌化合物之一，会被呼吸系统细胞色素 P450 (CYP) 2A13 生物活化，形成 DNA 加合物并诱发肺癌。抑制 CYP2A13 为烟草相关肺癌的化学预防提供了一种新策略。通过高通量筛选确定了 24 种 4-苄基吗啉支架类似物，并评估了它们与两种功能性人类 CYP2A 酶（CYP2A13 和 94% 相同的肝脏 CYP2A6）的结合和抑制作用。因此，选择性是化合物设计的一大挑战。导致 CYP2A13 选择性结合和抑制的一个关键特征是苄基正交位置的取代，有三种类似物对 CYP2A13 的选择性是 CYP2A6 的 25 倍。其中两种类似物的遗传毒性和 hERG 毒性均为阴性，在人肺微粒体中代谢稳定，但在人肝脏、小鼠和大鼠肺及肝微粒体中代谢迅速，可能是由于 CYP2B 介导的降解。一种模拟人类肺部的特异性基因敲除小鼠显示出化合物在肺部的持久性，提供了一个合适的测试模型。通过吸入给药的化合物可能在肺部有效，但在其他部位会被迅速清除，从而限制了全身接触。

  DOI：

  10.1007/s11095-013-1054-z

文献信息

• MORPHOLINES AS SELECTIVE INHIBITORS OF CYTOCHROME P450 2A13
  申请人：Scott Emily

  公开号：US20090137592A1

  公开（公告）日：2009-05-28

  A method of inhibiting formation of cancerous metabolites, of inhibiting cytochrome P450 2A13 from forming carcinogen metabolites, and/or inhibiting formation of cancerous lung cells in a subject can include: providing a morpholine compound that selectively interacts with cytochrome P450 2A13 over cytochrome P450 2A6; administering a therapeutically effective amount of the morpholine compound or derivative to the subject. The morpholine compound or derivative can be substantially more selective for interacting with the cytochrome P450 2A13 over the cytochrome P450 2A6. The morpholine compound or derivative can also be substantially non-interactive with other physiological components. The morpholine compound or derivative can include a structure that selectively interacts with cytochrome P450 2A13 over cytochrome P450 2A6, such as Compounds 1-34 of Formulas A-D.
• US8598165B2
  申请人：——

  公开号：US8598165B2

  公开（公告）日：2013-12-03
• US8962624B2
  申请人：——

  公开号：US8962624B2

  公开（公告）日：2015-02-24
• Benzylmorpholine Analogs as Selective Inhibitors of Lung Cytochrome P450 2A13 for the Chemoprevention of Lung Cancer in Tobacco Users
  作者：Linda C. Blake、Anuradha Roy、David Neul、Frank J. Schoenen、Jeffrey Aubé、Emily E. Scott

  DOI：10.1007/s11095-013-1054-z

  日期：2013.9

  4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), one of the most prevalent and procarcinogenic compounds in tobacco, is bioactivated by respiratory cytochrome P450 (CYP) 2A13, forming DNA adducts and initiating lung cancer. CYP2A13 inhibition offers a novel strategy for chemoprevention of tobacco-associated lung cancer. Twenty-four analogs of a 4-benzylmorpholine scaffold identified by high throughput screening were evaluated for binding and inhibition of both functional human CYP2A enzymes, CYP2A13 and the 94%-identical hepatic CYP2A6, whose inhibition is undesirable. Thus, selectivity is a major challenge in compound design. A key feature resulting in CYP2A13-selective binding and inhibition was substitution at the benzyl ortho position, with three analogs being >25-fold selective for CYP2A13 over CYP2A6. Two such analogs were negative for genetic and hERG toxicities and metabolically stable in human lung microsomes, but displayed rapid metabolism in human liver and in mouse and rat lung and liver microsomes, likely due to CYP2B-mediated degradation. A specialized knockout mouse mimicking the human lung demonstrates compound persistence in lung and provides an appropriate test model. Compound delivered by inhalation may be effective in the lung but rapidly cleared otherwise, limiting systemic exposure.

  4-(甲基亚硝基氨基)-1-(3-吡啶基)-1-丁酮（NNK）是烟草中最常见的致癌化合物之一，会被呼吸系统细胞色素 P450 (CYP) 2A13 生物活化，形成 DNA 加合物并诱发肺癌。抑制 CYP2A13 为烟草相关肺癌的化学预防提供了一种新策略。通过高通量筛选确定了 24 种 4-苄基吗啉支架类似物，并评估了它们与两种功能性人类 CYP2A 酶（CYP2A13 和 94% 相同的肝脏 CYP2A6）的结合和抑制作用。因此，选择性是化合物设计的一大挑战。导致 CYP2A13 选择性结合和抑制的一个关键特征是苄基正交位置的取代，有三种类似物对 CYP2A13 的选择性是 CYP2A6 的 25 倍。其中两种类似物的遗传毒性和 hERG 毒性均为阴性，在人肺微粒体中代谢稳定，但在人肝脏、小鼠和大鼠肺及肝微粒体中代谢迅速，可能是由于 CYP2B 介导的降解。一种模拟人类肺部的特异性基因敲除小鼠显示出化合物在肺部的持久性，提供了一个合适的测试模型。通过吸入给药的化合物可能在肺部有效，但在其他部位会被迅速清除，从而限制了全身接触。