1-ethyl-4-(6-methoxy-5-nitropyridin-2-yl)piperazine

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: 1-ethyl-4-(6-methoxy-5-nitropyridin-2-yl)piperazine
• 英文别名: 1-Ethyl-4-(6-methoxy-5-nitropyridin-2-yl)piperazine
• 化学式: C₁₂H₁₈N₄O₃
• 分子量: 266.3
• InChiKey: KTVAHTDICCLYRP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  74.4
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-ethyl-4-(6-methoxy-5-nitropyridin-2-yl)piperazine 在 palladium 10% on activated carbon 、 氢气 作用下， 以 乙醇 为溶剂， 反应 5.0h， 生成 6-(4-ethylpiperazin-1-yl)-2-methoxypyridin-3-amine
  参考文献：
  名称：

  设计，合成和生物评价新型蝶啶酮衍生物作为PLK1和BRD4的有效双重抑制剂

  摘要：

  为了开发单个分子对PLK1和BRD4溴结构域的新型同时抑制作用，设计，合成和评估了三个系列的新型蝶啶酮衍生物的生物活性。大多数化合物对A549，HCT116，PC-3和MCF-7细胞系表现出中度至优异的细胞毒活性。最有前途的化合物III 4对四种细胞株具有较高的抗增殖作用，IC 50值分别为1.27μM，1.36μM，3.85μM和4.06μM。酶法鉴定为III 4作为有效的PLK1和BRD4双重抑制剂，抑制百分率分别为96.6和59.1。此外，为了阐明目标化合物的抗癌机理，进行了生物活性的探索。结果显示，化合物III 4明显抑制HCT-116细胞系的增殖，诱导线粒体膜电位大大降低，导致癌细胞凋亡，抑制肿瘤细胞迁移，并阻滞HCT116细胞的S期。

  DOI：

  10.1039/d0nj03477k
• 作为产物：
  描述：

  2,6-二氯-3-硝基吡啶 在 sodium hydride 、 potassium carbonate 作用下， 以 四氢呋喃 、 mineral oil 为溶剂， 反应 9.0h， 生成 1-ethyl-4-(6-methoxy-5-nitropyridin-2-yl)piperazine
  参考文献：
  名称：

  Dual potent ALK and ROS1 inhibitors combating drug-resistant mutants: Synthesis and biological evaluation of aminopyridine-containing diarylaminopyrimidine derivatives

  摘要：

  To identify ALK and ROS1 dual inhibitors conferring resistance to ALK secondary mutations, especially 'gatekeeper' L1196 M and the most predominant ceritinib-resistant G1202R mutations, a series of novel 2,4-diarylaminopyrimidine analogues were designed and synthesized by incorporating 2-alkoxy-6-alicyclic aminopyridinyl motifs. The biological evaluations on cellular and enzymatic assays led to identification of compound F-1, which turned out to be effective against ALK(WT), ROS1(WT), ALK(L1196M) and ALK(G1202R) kinases with IC50 of 2.1 nM, 2.3 nM, 1.3 nM and 3.9 nM, respectively, superior to crizotinib and ceritinib. Moreover, F-1 exhibited significant cytotoxicity on ALK-addicted Karpas299, H2228, and Ba/F3 cell expressing G1202R mutant, as well as ROS1-positive HCC78 cell with IC50 values ranging from 10 nM to 43 nM. Notably, F-1 was capable of suppressing phospho-ALK and its relative downstream signaling pathways, and eventually, inducing cell apoptosis in a dose-dependent manner in Karpas-299 cell. Together, F-1 is validated as a promising ALK/ROS1 dual inhibitor great potential for G1202R ALK mutation cancers. (C) 2018 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2018.09.012

文献信息

• [EN] ACUTE MYELOID LEUKEMIA TARGETED THERAPEUTIC AGENT WITH REDUCED DRUG SIDE EFFECTS<br/>[FR] AGENT THÉRAPEUTIQUE CIBLANT LA LEUCÉMIE MYÉLOÎDE AIGUË AYANT DES EFFETS SECONDAIRES MÉDICAMENTEUX RÉDUITS<br/>[KO] 약물 부작용이 감소된 급성골수성백혈병 표적치료제
  申请人：KOREA INST SCI & TECH

  公开号：WO2016006921A1

  公开（公告）日：2016-01-14

  본 발명은 급성골수성백혈병 표적치료제에 관한 것으로서, 급성골수성백혈병의 저해활성과 FLT3 점돌연변이종에 대한 저해활성을 가지고 있는 약물 부작용이 감소된 급성골수성백혈병 치료, 예방 및 경감에 유용하다.
• Design, synthesis and biological evaluation of novel pteridinone derivatives as potent dual inhibitors of PLK1 and BRD4
  作者：Yinliang Qi、Le Xu、Zhiwei Li、Ping Gong、Tao Hu、Bixi Yin、Mingze Qin、Yajing Liu、Yanfang Zhao、Yunlei Hou

  DOI：10.1039/d0nj03477k

  日期：——

  To develop novel simultaneous inhibition of PLK1 and BRD4 bromodomain by a single molecule, three series of novel pteridinone derivatives were designed, synthesized and evaluated for their biological activity. Most compounds exhibited moderate to excellent cytotoxic activity against A549, HCT116, PC-3 and MCF-7 cell lines. The most promising compound III4 showed high antiproliferative effects on four

  为了开发单个分子对PLK1和BRD4溴结构域的新型同时抑制作用，设计，合成和评估了三个系列的新型蝶啶酮衍生物的生物活性。大多数化合物对A549，HCT116，PC-3和MCF-7细胞系表现出中度至优异的细胞毒活性。最有前途的化合物III 4对四种细胞株具有较高的抗增殖作用，IC 50值分别为1.27μM，1.36μM，3.85μM和4.06μM。酶法鉴定为III 4作为有效的PLK1和BRD4双重抑制剂，抑制百分率分别为96.6和59.1。此外，为了阐明目标化合物的抗癌机理，进行了生物活性的探索。结果显示，化合物III 4明显抑制HCT-116细胞系的增殖，诱导线粒体膜电位大大降低，导致癌细胞凋亡，抑制肿瘤细胞迁移，并阻滞HCT116细胞的S期。
• Dual potent ALK and ROS1 inhibitors combating drug-resistant mutants: Synthesis and biological evaluation of aminopyridine-containing diarylaminopyrimidine derivatives
  作者：Ming Guo、Daiying Zuo、Junlong Zhang、Lingyun Xing、Wenfeng Gou、Feng Jiang、Nan Jiang、Dajun Zhang、Xin Zhai

  DOI：10.1016/j.ejmech.2018.09.012

  日期：2018.10

  To identify ALK and ROS1 dual inhibitors conferring resistance to ALK secondary mutations, especially 'gatekeeper' L1196 M and the most predominant ceritinib-resistant G1202R mutations, a series of novel 2,4-diarylaminopyrimidine analogues were designed and synthesized by incorporating 2-alkoxy-6-alicyclic aminopyridinyl motifs. The biological evaluations on cellular and enzymatic assays led to identification of compound F-1, which turned out to be effective against ALK(WT), ROS1(WT), ALK(L1196M) and ALK(G1202R) kinases with IC50 of 2.1 nM, 2.3 nM, 1.3 nM and 3.9 nM, respectively, superior to crizotinib and ceritinib. Moreover, F-1 exhibited significant cytotoxicity on ALK-addicted Karpas299, H2228, and Ba/F3 cell expressing G1202R mutant, as well as ROS1-positive HCC78 cell with IC50 values ranging from 10 nM to 43 nM. Notably, F-1 was capable of suppressing phospho-ALK and its relative downstream signaling pathways, and eventually, inducing cell apoptosis in a dose-dependent manner in Karpas-299 cell. Together, F-1 is validated as a promising ALK/ROS1 dual inhibitor great potential for G1202R ALK mutation cancers. (C) 2018 Elsevier Masson SAS. All rights reserved.