N-(2-amino-1,2-dicyano-vinyl)-formimydic acid ethyl ester | 133123-63-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 甲亚胺酸及其衍生物
• 英文名称: N-(2-amino-1,2-dicyano-vinyl)-formimydic acid ethyl ester
• 英文别名: N-(2-amino-1,2-dicyanovinyl)-formimydic acid ester；ethyl N-(2-amino-1,2-dicyanovinyl)formimidate；ethyl N-(2-amino-1,2-dicyanoethenyl)methanimidate
• CAS: 133123-63-4
• 化学式: C₇H₈N₄O
• 分子量: 164.167
• InChiKey: WAKHKSLIDJTOKC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  12
• 可旋转键数：
  3
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  95.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  N-(2-amino-1,2-dicyano-vinyl)-formimydic acid ethyl ester 在 硫酸 、 aniline hydrochloride 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 乙醇 、 乙腈 为溶剂， 反应 12.0h， 生成 5-Benzyl-11-[(4-methoxyphenyl)methyl]-3,5,7,9,11,13-hexazatricyclo[8.3.0.02,6]trideca-1(10),2,6,8,12-pentaen-4-one
  参考文献：
  名称：

  Structure-based drug design and potent anti-cancer activity of tricyclic 5:7:5-fused diimidazo[4,5-d:4′,5′-f][1,3]diazepines

  摘要：

  Judicial structural modifications of 5: 7-fused ring-expanded nucleosides (RENs), based on molecular modeling studies with one of its known targets, human RNA helicase (hDDX3), led to the lead, novel, 5:7-5-fused tricyclic heterocycle (1). The latter exhibited promising broad-spectrum in vitro anti-cancer activity against a number of cancer cell lines screened. This paper describes our systematic, albeit limited, structure-activity relationship (SAR) studies on this lead compound, which produced a number of analogs with broad-spectrum in vitro anti-cancer activities against lung, breast, prostate, and ovarian cancer cell lines, in particular compounds 15i, 15j, 15m and 15n which showed IC50 values in submicromolar to micromolar range, and are worthy of further explorations. The SAR data also enabled us to propose a tentative SAR model for future SAR efforts for ultimate realization of optimally active and minimally toxic anti-cancer compounds based on the diimidazo[4,5-d:4',5'-f][1,3]diazepine structural skeleton of the lead compound 1. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2012.11.050
• 作为产物：
  描述：

  原甲酸三乙酯 、 2,3-diaminomaleonitrile 以 1,4-二氧六环 为溶剂， 反应 6.0h， 生成 N-(2-amino-1,2-dicyano-vinyl)-formimydic acid ethyl ester
  参考文献：
  名称：

  Design and Synthesis of Non-Covalent Imidazo[1,2-a]quinoxaline-Based Inhibitors of EGFR and Their Anti-Cancer Assessment

  摘要：

  一系列30个非共价的咪唑[1,2-a]喹喔啉基表皮生长因子受体（EGFR）抑制剂被设计并合成。化合物的EGFR抑制评估（针对野生型）数据显示6b、7h、7j、9a和9c作为有效的EGFRWT抑制剂，IC50值分别为211.22、222.21、193.18、223.32和221.53纳摩尔，与厄洛替尼（221.03纳摩尔）相当，作为阳性对照。此外，当化合物对携带EGFRWT的癌细胞系进行测试时，表现出优秀的抗增殖活性；A549，非小细胞肺癌（NSCLC），HCT-116（结肠癌），MDA-MB-231（乳腺癌）以及携带EGFRL858R/T790M的吉非替尼耐药NSCLC细胞系H1975。特别是，化合物6b对吉非替尼耐药的H1975细胞表现出显著的抑制潜力（IC50 = 3.65微摩尔），相比之下，吉非替尼的IC50值大于20微摩尔。此外，分子对接揭示了6b与EGFR结构域（野生型和突变型）的结合方式，表明了抑制的基础。此外，还报道了其对A549肺癌细胞的氧化还原调节、线粒体膜电位、细胞周期分析和细胞死亡方式的影响。

  DOI：

  10.3390/molecules26051490

文献信息

• [EN] MACROCYCLIC PURINES FOR THE TREATMENT OF VIRAL INFECTIONS<br/>[FR] PURINES MACROCYCLIQUES DESTINÉES AU TRAITEMENT D'INFECTIONS VIRALES
  申请人：JANSSEN R & D IRELAND

  公开号：WO2014009509A1

  公开（公告）日：2014-01-16

  This invention relates macrocyclic purine derivatives having formula (I), processes for their preparation, pharmaceutical compositions, and their use in treating viral infections.

  这项发明涉及具有式(I)的大环嘌呤衍生物，其制备方法，药物组合物以及它们在治疗病毒感染中的应用。
• [EN] PURINE DERIVATIVES FOR THE TREATMENT OF VIRAL INFECTIONS<br/>[FR] DÉRIVÉS DE PURINE POUR LE TRAITEMENT D'INFECTIONS VIRALES
  申请人：JANSSEN R & D IRELAND

  公开号：WO2013068438A1

  公开（公告）日：2013-05-16

  The present invention relates to purine derivatives of formula (I), processes for their preparation, pharmaceutical compositions, and their use in treating viral infections.

  本发明涉及式(I)的嘌呤衍生物，其制备方法，药物组合物以及它们在治疗病毒感染中的应用。
• A Simple Precursor for Highly Functionalized Fused Imidazo[4,5-b]pyridines and Imidazo[4,5-b]-1,8-naphthyridine
  作者：Omar Al-duaij、Magdi Zaki、Abdel-Rhman El Gazzar

  DOI：10.3390/molecules21121646

  日期：——

  5-amino-3-(substituted benzyl)-6,7-dicyano-3H-imidazo[4,5-b]pyridines 5 and 6,8-diamino-3-(4-substituted benzyl)-3H-imidazo[4,5-b]-1,8-naphthyridine-7,9-dicarbonitrile 6, respectively, when the reaction was carried out in the absence of a base, or to 5,7-diamino-3-(4-alkyl aryl)-3H-imidazo[4,5-b]pyridine-6-carbonitrile 8, and 6,8,9-triamino-3-(4-substitutedbenzyl)-3H-imidazo[4,5-b]-1,8-naphthyridine-7-carbonitrile 10

  在温和的实验条件下，使1-烷基芳基-5-氨基-4-（氰基甲酰亚胺基）咪唑4与丙二腈和2-氨基-1,1,3-丙烯三腈反应，生成5-氨基-3-（取代的苄基） -6,7-二氰基-3H-咪唑并[4,5-b]吡啶5和6,8-二氨基-3-（4-取代的苄基）-3H-咪唑并[4,5-b] -1,8-萘啶-7,9-二腈6，当反应在没有碱的情况下进行时，或与5,7-二氨基-3-（4-烷基芳基）-3H-咪唑并[4,5-b在存在下，]吡啶-6-腈8和6,8,9-三氨基-3-（4-取代的苄基）-3H-咪唑并[4,5-b] -1,8-萘啶-7-腈10 1,8-二氮杂双环（5.4.0）十一碳-7-烯（DBU）。这两个反应都是由丙二腈或2-氨基-1,1,3-丙烯三腈的亲核攻击形成的加合物演化为氰基甲亚胺基取代基的碳。在丙二腈阴离子的情况下，当该反应在DBU存在下进行时，分离出5-氨基-1-烷基芳基-4-（1-氨基-2,2
• In Vivo Anticancer Evaluation of 6b, a Non-Covalent Imidazo[1,2-a]quinoxaline-Based Epidermal Growth Factor Receptor Inhibitor against Human Xenograft Tumor in Nude Mice
  作者：Zahid Rafiq Bhat、Manvendra Kumar、Nisha Sharma、Umesh Prasad Yadav、Tashvinder Singh、Gaurav Joshi、Brahmam Pujala、Mohd Raja、Joydeep Chatterjee、Kulbhushan Tikoo、Sandeep Singh、Raj Kumar

  DOI：10.3390/molecules27175540

  日期：——

  Tyrosine kinase inhibitors are validated therapeutic agents against EGFR-mutated non-small cell lung cancer (NSCLC). However, the associated critical side effects of these agents are inevitable, demanding more specific and efficient targeting agents. Recently, we have developed and reported a non-covalent imidazo[1,2-a]quinoxaline-based EGFR inhibitor (6b), which showed promising inhibitory activity against the gefitinib-resistant H1975(L858R/T790M) lung cancer cell line. In the present study, we further explored the 6b compound in vivo by employing the A549-induced xenograft model in nude mice. The results indicate that the administration of the 6b compound significantly abolished the growth of the tumor in the A549 xenograft nude mice. Whereas the control mice bearing tumors displayed a declining trend in the survival curve, treatment with the 6b compound improved the survival profile of mice. Moreover, the histological examination showed the cancer cell cytotoxicity of the 6b compound was characterized by cytoplasmic destruction observed in the stained section of the tumor tissues of treated mice. The immunoblotting and qPCR results further signified that 6b inhibited EGFR in tissue samples and consequently altered the downstream pathways mediated by EGFR, leading to a reduction in cancer growth. Therefore, the in vivo findings were in corroboration with the in vitro results, suggesting that 6b possessed potential anticancer activity against EGFR-dependent lung cancer. 6b also exhibited good stability in human and mouse liver microsomes.

  酪氨酸激酶抑制剂是治疗表皮生长因子受体（EGFR）突变的非小细胞肺癌（NSCLC）的有效药物。然而，这些药物不可避免地会产生严重的副作用，因此需要更特异、更高效的靶向药物。最近，我们开发并报道了一种基于咪唑并[1,2-a]喹喔啉的非共价表皮生长因子受体抑制剂（6b），它对吉非替尼耐药的 H1975(L858R/T790M) 肺癌细胞系具有良好的抑制活性。在本研究中，我们采用 A549 诱导的裸鼠异种移植模型，进一步探讨了 6b 复合物的体内活性。结果表明，给药 6b 复合物能明显抑制 A549 异种移植裸鼠的肿瘤生长。携带肿瘤的对照组小鼠的生存曲线呈下降趋势，而使用 6b 化合物治疗则改善了小鼠的生存状况。此外，组织学检查显示，6b 复合物的癌细胞毒性表现在治疗小鼠肿瘤组织染色切片中观察到的细胞质破坏。免疫印迹和 qPCR 结果进一步表明，6b 抑制了组织样本中的表皮生长因子受体，从而改变了表皮生长因子受体介导的下游通路，导致癌症生长减弱。因此，体内研究结果与体外研究结果相吻合，表明 6b 对表皮生长因子受体依赖性肺癌具有潜在的抗癌活性。6b 在人和小鼠肝脏微粒体中也表现出良好的稳定性。
• Imidazolylpyrrolone‐Based Small Molecules as Anticancer Agents for Renal Cell Carcinoma
  作者：Ana Sousa、Olívia Pontes、Juliana Andrade、Fátima Baltazar、Marta Costa、Fernanda Proença

  DOI：10.1002/cmdc.202200519

  日期：2023.1.17

  selection of imidazopyrrolopyridines annotated as potentially active on cancer-related target proteins were prepared by a novel in-house synthetic approach. The molecules were screened using the renal cell carcinoma cell line model (A498 and 786-O cell lines). Two compounds exhibited low IC50 values with good selectivity profiles, and are promising candidates for the treatment of this unmet medical need.

  通过一种新的内部合成方法制备了一系列被注释为对癌症相关靶蛋白具有潜在活性的咪唑并吡咯并吡啶。使用肾细胞癌细胞系模型（A498 和 786-O 细胞系）筛选分子。两种化合物表现出低 IC 50值和良好的选择性，是治疗这一未满足的医疗需求的有前途的候选者。