2-((4-(2-(4-chlorophenoxy)ethanoyl)piperazin-1-yl)methyl)-3-(2-isopropoxy-5-(2-(4-methylpiperazin-1-yl)ethanoyl)phenyl)quinazolin-4(3H)-one

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 2-((4-(2-(4-chlorophenoxy)ethanoyl)piperazin-1-yl)methyl)-3-(2-isopropoxy-5-(2-(4-methylpiperazin-1-yl)ethanoyl)phenyl)quinazolin-4(3H)-one
• 英文别名: 2-[[4-[2-(4-Chlorophenoxy)acetyl]piperazin-1-yl]methyl]-3-[5-[2-(4-methylpiperazin-1-yl)acetyl]-2-propan-2-yloxyphenyl]quinazolin-4-one；2-[[4-[2-(4-chlorophenoxy)acetyl]piperazin-1-yl]methyl]-3-[5-[2-(4-methylpiperazin-1-yl)acetyl]-2-propan-2-yloxyphenyl]quinazolin-4-one
• 化学式: C₃₇H₄₃ClN₆O₅
• 分子量: 687.239
• InChiKey: BKXVJIGHOPYEME-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  49
• 可旋转键数：
  11
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  98.2
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  1-(4-isopropoxy-3-nitrophenyl)acetone 在 盐酸 、 4-二甲氨基吡啶 、 N-氯代丁二酰亚胺 、 对甲苯磺酸 、 N,N-二异丙基乙胺 、 tin(ll) chloride 、 三氯化磷 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 43.2h， 生成 2-((4-(2-(4-chlorophenoxy)ethanoyl)piperazin-1-yl)methyl)-3-(2-isopropoxy-5-(2-(4-methylpiperazin-1-yl)ethanoyl)phenyl)quinazolin-4(3H)-one
  参考文献：
  名称：

  Incorporation of metabolically stable ketones into a small molecule probe to increase potency and water solubility

  摘要：

  Introducing a reactive carbonyl to a scaffold that does not otherwise have an electrophilic functionality to create a reversible covalent inhibitor is a potentially useful strategy for enhancing compound potency. However, aldehydes are metabolically unstable, which precludes the use of this strategy for compounds to be tested in animal models or in human clinical studies. To overcome this limitation, we designed ketone-based functionalities capable of forming reversible covalent adducts, while displaying high metabolic stability, and imparting improved water solubility to their pendant scaffold. We tested this strategy on the ferroptosis inducer and experimental therapeutic erastin, and observed substantial increases in compound potency. In particular, a new carbonyl erastin analog, termed IKE, displayed improved potency, solubility and metabolic stability, thus representing an ideal candidate for future in vivo cancer therapeutic applications. (C) 2015 Published by Elsevier Ltd.

  DOI：

  10.1016/j.bmcl.2015.07.018

文献信息

• [EN] CARBONYL ERASTIN ANALOGS AND THEIR USE<br/>[FR] ANALOGUES CARBONYLÉS DE L'ÉRASTINE ET LEUR UTILISATION
  申请人：UNIV COLUMBIA

  公开号：WO2015109009A1

  公开（公告）日：2015-07-23

  The present invention provides, inter alia, compounds having the structure of formula (I): Compositions containing such compounds are also provided. Methods for using such compounds or compositions for treating or ameliorating the effects of a cancer having a cell that harbors an oncogenic RAS mutation, for modulating a lipoxygenase in a ferroptosis cell death pathway, and for depleting reduced glutathione (GSH) in a cell harboring an oncogenic RAS mutation are further provided.

  本发明提供了具有以下结构的化合物，其中包含这些化合物的组合物也提供了。还提供了使用这些化合物或组合物用于治疗或改善携带致癌RAS突变细胞的癌症的效果，用于调节铁死亡细胞途径中的一种脂氧合酶，以及用于消耗携带致癌RAS突变细胞中的还原型谷胱甘肽（GSH）的方法。
• CARBONYL ERASTIN ANALOGS AND THEIR USE
  申请人：THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK

  公开号：US20160332974A1

  公开（公告）日：2016-11-17

  The present invention provides, inter alia, compounds having the structure of formula (I): Compositions containing such compounds are also provided. Methods for using such compounds or compositions for treating or ameliorating the effects of a cancer having a cell that harbors an oncogenic RAS mutation, for modulating a lipoxygenase in a ferroptosis cell death pathway, and for depleting reduced glutathione (GSH) in a cell harboring an oncogenic RAS mutation are further provided.

  本发明提供具有以下结构的化合物，其中公式为(I)：还提供包含这些化合物的组合物。还提供了使用这些化合物或组合物来治疗或改善携带致癌RAS突变细胞的癌症效果，调节铁死亡细胞途径中的一种脂氧合酶，以及在携带致癌RAS突变细胞中耗尽还原型谷胱甘肽（GSH）的方法。
• METHODS OF CANCER TREATMENT
  申请人：Ferro Therapeutics, Inc.

  公开号：US20200138829A1

  公开（公告）日：2020-05-07

  The present disclosure relates to a method of treating a subject with cancer with a ferroptosis inducer, including use of the ferroptosis inducer in combination with a second therapeutic agent.
• US9938245B2
  申请人：——

  公开号：US9938245B2

  公开（公告）日：2018-04-10
• Incorporation of metabolically stable ketones into a small molecule probe to increase potency and water solubility
  作者：Marie-Helene Larraufie、Wan Seok Yang、Elise Jiang、Ajit G. Thomas、Barbara S. Slusher、Brent R. Stockwell

  DOI：10.1016/j.bmcl.2015.07.018

  日期：2015.11

  Introducing a reactive carbonyl to a scaffold that does not otherwise have an electrophilic functionality to create a reversible covalent inhibitor is a potentially useful strategy for enhancing compound potency. However, aldehydes are metabolically unstable, which precludes the use of this strategy for compounds to be tested in animal models or in human clinical studies. To overcome this limitation, we designed ketone-based functionalities capable of forming reversible covalent adducts, while displaying high metabolic stability, and imparting improved water solubility to their pendant scaffold. We tested this strategy on the ferroptosis inducer and experimental therapeutic erastin, and observed substantial increases in compound potency. In particular, a new carbonyl erastin analog, termed IKE, displayed improved potency, solubility and metabolic stability, thus representing an ideal candidate for future in vivo cancer therapeutic applications. (C) 2015 Published by Elsevier Ltd.