4'-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-[3,6'-biquinoline]-3'-carboxamide hydrochloride

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 4'-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-[3,6'-biquinoline]-3'-carboxamide hydrochloride
• 英文别名: MXD-42；4-[4-Piperazin-1-yl-3-(trifluoromethyl)anilino]-6-quinolin-3-ylquinoline-3-carboxamide;hydrochloride；4-[4-piperazin-1-yl-3-(trifluoromethyl)anilino]-6-quinolin-3-ylquinoline-3-carboxamide;hydrochloride
• 化学式: C₃₀H₂₅F₃N₆O*ClH
• 分子量: 579.024
• InChiKey: HHZIEIHPROHCFW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.14
• 重原子数：
  41
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  96.2
• 氢给体数：
  4
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  4'-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-[3,6'-biquinoline]-3'-carboxamide hydrochloride 在 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 9.0h， 生成 6-(quinoline-3-yl)-4-((4-(4-(γ-aminobutyryl)piperazino)-3-(trifluoromethyl)phenyl)amino)quinoline-3-ylformylamine
  参考文献：
  名称：

  偶联的mTOR / MEK双功能抑制剂作为潜在的多药理抗癌剂：原型化合物的发现

  摘要：

  mTOR / MEK双功能抑制剂具有克服PI3K / Akt / mTOR（PAM）与Ras / MEK / ERK途径之间的串扰引起的耐药性的潜力。在本文中，我们报告了共轭双靶分子化合物13作为原型mTOR / MEK双功能抑制剂的发现。它显示出对mTOR和MEK1的适度高抑制活性，IC 50值分别为0.19μM和0.98μM。特别是，它对A549（GI 50  = 4.66μM）和HCT116（GI 50）均表现出有吸引力的抗增殖活性 = 5.47μM）细胞系。据我们所知，它是mTOR / MEK共轭双功能抑制剂的第一个实例。此外，从这项原理验证研究中，很明显，可以通过将mTOR激酶抑制剂共价连接至变构MEK抑制剂来实现mTOR和MEK的单剂双重抑制。

  DOI：

  10.1007/s00044-020-02502-x
• 作为产物：
  描述：

  tert-butyl 4-(4-nitro-2-(trifluoromethyl)phenyl)piperazine-1-carboxylate 在 盐酸 、 四(三苯基膦)钯 、 palladium 10% on activated carbon 、 氨 、 氢气 、 sodium acetate 、 potassium carbonate 、 溶剂黄146 作用下， 以 1,4-二氧六环 、 甲醇 、 乙醇 、 水 、 乙酸乙酯 为溶剂， 反应 19.5h， 生成 4'-((4-(piperazin-1-yl)-3-(trifluoromethyl)phenyl)amino)-[3,6'-biquinoline]-3'-carboxamide hydrochloride
  参考文献：
  名称：

  Discovery of novel quinoline-based mTOR inhibitors via introducing intra-molecular hydrogen bonding scaffold (iMHBS): The design, synthesis and biological evaluation

  摘要：

  A series of quinoline derivatives featuring the novelty of introducing intra-molecular hydrogen bonding scaffold (iMHBS) were designed, synthesized and biologically evaluated for their mTOR inhibitory activity, as well as anti-proliferative efficacies against HCT-116, PC-3 and MCF-7 cell lines. As a result, six compounds exhibited significant inhibition against mTOR with IC50 values below 35 nM. Compound 15a, the most potent mTOR inhibitor reported herein (IC50 = 14 nM), also displayed the most favorable cellular activities, with the IC50 values of 0.46, 0.61 and 0.24 mu M against HCT-116, PC-3 and MCF-7, respectively. Besides, several compounds in this series were identified to be selective over class I PI3Ks. Further western blot analysis of 16b, a representative compound in this series, highlighted their advantage in surmounting the S6K/IRS1/PI3K negative feedback loop upon dual inhibition of mTORC1 and mTORC2. In addition to the remarkable activity, 15a demonstrated acceptable stability in simulated gastric fluid (SGF), simulated intestinal fluid (SIF) and liver microsome, thereby being valuable for extensive in vivo investigation. (c) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2015.11.003

文献信息

• 一类新型mTOR/MEK双靶点抑制剂及其用途
  申请人：安徽中医药大学

  公开号：CN111909139A

  公开（公告）日：2020-11-10

  本发明涉及药物化学领域，具体涉及结构通式为I的双靶标分子、其制备方法、其药学上可接受的盐，以及含有它们的药物组合物，用作抗肿瘤用途。药效学评价证明，本发明涉及的双靶标分子可同时抑制mTOR和MEK激酶，且对恶性肿瘤细胞株具有良好的抗增殖活性，有望用于癌症治疗。
• A conjugated mTOR/MEK bifunctional inhibitor as potential polypharmacological anticancer agent: the prototype compound discovery
  作者：Qiangqiang Tao、Fang Fang、Jiaming Li、Yong Wang、Can Zhao、Jingtai Liang、Xiaodong Ma、Hao Wang

  DOI：10.1007/s00044-020-02502-x

  日期：2020.3

  To our knowledge, it has been the first example of a conjugated mTOR/MEK bifunctional inhibitor. In addition, from this proof-of-principle study, it has become evident that the single-agent dual inhibition of mTOR and MEK can be fulfilled via covalently attaching mTOR kinase inhibitor to an allosteric MEK inhibitor.

  mTOR / MEK双功能抑制剂具有克服PI3K / Akt / mTOR（PAM）与Ras / MEK / ERK途径之间的串扰引起的耐药性的潜力。在本文中，我们报告了共轭双靶分子化合物13作为原型mTOR / MEK双功能抑制剂的发现。它显示出对mTOR和MEK1的适度高抑制活性，IC 50值分别为0.19μM和0.98μM。特别是，它对A549（GI 50  = 4.66μM）和HCT116（GI 50）均表现出有吸引力的抗增殖活性 = 5.47μM）细胞系。据我们所知，它是mTOR / MEK共轭双功能抑制剂的第一个实例。此外，从这项原理验证研究中，很明显，可以通过将mTOR激酶抑制剂共价连接至变构MEK抑制剂来实现mTOR和MEK的单剂双重抑制。
• Discovery of novel quinoline-based mTOR inhibitors via introducing intra-molecular hydrogen bonding scaffold (iMHBS): The design, synthesis and biological evaluation
  作者：Xiaodong Ma、Xiaoqing Lv、Ni Qiu、Bo Yang、Qiaojun He、Yongzhou Hu

  DOI：10.1016/j.bmc.2015.11.003

  日期：2015.12

  A series of quinoline derivatives featuring the novelty of introducing intra-molecular hydrogen bonding scaffold (iMHBS) were designed, synthesized and biologically evaluated for their mTOR inhibitory activity, as well as anti-proliferative efficacies against HCT-116, PC-3 and MCF-7 cell lines. As a result, six compounds exhibited significant inhibition against mTOR with IC50 values below 35 nM. Compound 15a, the most potent mTOR inhibitor reported herein (IC50 = 14 nM), also displayed the most favorable cellular activities, with the IC50 values of 0.46, 0.61 and 0.24 mu M against HCT-116, PC-3 and MCF-7, respectively. Besides, several compounds in this series were identified to be selective over class I PI3Ks. Further western blot analysis of 16b, a representative compound in this series, highlighted their advantage in surmounting the S6K/IRS1/PI3K negative feedback loop upon dual inhibition of mTORC1 and mTORC2. In addition to the remarkable activity, 15a demonstrated acceptable stability in simulated gastric fluid (SGF), simulated intestinal fluid (SIF) and liver microsome, thereby being valuable for extensive in vivo investigation. (c) 2015 Elsevier Ltd. All rights reserved.