N-(4-aminophenyl)-4-(quinolin-4-ylamino)benzamide | 1535187-97-3

• 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: N-(4-aminophenyl)-4-(quinolin-4-ylamino)benzamide
• CAS: 1535187-97-3
• 化学式: C₂₂H₁₈N₄O
• 分子量: 354.411
• InChiKey: UCIZEGZPSMUBGV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  80
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(4-aminophenyl)-4-(quinolin-4-ylamino)benzamide 、 氯甲酸苄酯 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 1.5h， 以72%的产率得到benzyl (4-(4-(quinolin-4-ylamino) benzamido)phenyl)carbamate
  参考文献：
  名称：

  Identification of a novel quinoline-based DNA demethylating compound highly potent in cancer cells

  摘要：

  摘要： DNA甲基转移酶（DNMTs）是一种表观遗传酶，参与胚胎发育、细胞分化、上皮向间充质转化和基因表达的调控，其过度表达或增强的催化活性已广泛报道与癌症的发生和进展有关。迄今为止，已批准两种DNMT抑制剂（DNMTi），5-氮杂胞苷（5-AZA）和5-氮杂-2'-去氧胞苷（DAC），用于治疗骨髓增生异常综合征和急性髓系白血病。然而，它们在化学上不稳定且对健康细胞有毒性，因此迫切需要发现新的DNMTi。 在这里，我们报告了一种新的喹啉类分子MC3353，作为一种非核苷酸抑制剂和DNMT下调剂，这种化合物能够在启动子去甲基化实验中，诱导HCT116细胞中增强型绿色荧光蛋白（EGFP）基因表达，并在KG-1细胞中的巨细胞病毒（CMV）启动子驱动的荧光素酶报告系统中诱导转录。此外，MC3353在0.5μM的浓度下处理48小时后，在HCT116结肠癌细胞上显示出强烈的抗增殖活性。在较高的剂量下，该化合物在双重DNMT敲除HCT116细胞中产生细胞毒性效应。MC3353还在不同的癌细胞系（KG-1和U-937急性髓系白血病、RAJI Burkitt淋巴瘤、PC-3前列腺癌和MDA-MB-231乳腺癌）上进行筛选，其中在处理48小时后，IC50值范围从0.3到0.9μM，抑制细胞增殖并降低细胞活力。与健康细胞模型相比，MC3353在较低浓度下诱导细胞凋亡（例如U-937和KG-1细胞）或坏死（例如RAJI细胞）。重要的是，除了主要的DNMT3A酶抑制外，MC3353还能够在选定的HCT116和PC-3细胞系中下调DNMT3A蛋白水平。此外，该化合物在PC-3和HCT116细胞中通过诱导E-钙粘蛋白并减少基质金属蛋白酶（MMP2）mRNA和蛋白水平，提供了上皮-间充质转化（EMT）的损害。最后，在一系列原发性骨肉瘤细胞系上进行测试，MC3353明显抑制细胞生长，IC50值范围从1.1到2.4μM。有趣的是，在Saos-2骨肉瘤细胞中，MC3353诱导了基因和矿化基质的表达，作为骨肉瘤向成骨细胞分化的证据。 结论： 本研究描述了MC3353作为一种新的DNMTi，其在细胞去甲基化能力方面比5-AZA和DAC更强，提供了沉默的泛素C端水解酶L1（UCHL1）基因的重新激活。MC3353在多种癌细胞类型中显示出剂量和时间依赖的抗增殖活性，诱导细胞死亡并通过E-钙粘蛋白和MMP2调节影响EMT。此外，该化合物在原发性骨肉瘤细胞模型中也证明了其有效性，通过调节与成骨细胞分化有关的基因。

  DOI：

  10.1186/s13148-019-0663-8
• 作为产物：
  描述：

  4-氯喹啉 在 盐酸 、 benzotriazol-1-yloxyl-tris-(pyrrolidino)-phosphonium hexafluorophosphate 、 三乙胺 、 potassium hydroxide 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.5h， 生成 N-(4-aminophenyl)-4-(quinolin-4-ylamino)benzamide
  参考文献：
  名称：

  Selective Non-nucleoside Inhibitors of Human DNA Methyltransferases Active in Cancer Including in Cancer Stem Cells

  摘要：

  DNA methyltransferases (DNMTs) are important enzymes involved in epigenetic control of gene expression and represent valuable targets in cancer chemotherapy. A number of nucleoside DNMT inhibitors (DNMTi) have been studied in cancer, including in cancer stem cells, and two of them (azacytidine and decitabine) have been approved for treatment of myelodysplastic syndromes. However, only a few non-nucleoside DNMTi have been identified so far, and even fewer have been validated in cancer. Through a process of hit-to-lead optimization, we report here the discovery of compound 5 as a potent non-nucleoside DNMTi that is also selective toward other Ado Met-dependent protein methyltransferases. Compound 5 was potent at single-digit micromolar concentrations against a panel of cancer cells and was less toxic in peripheral blood mononuclear cells than two other compounds tested. In mouse medulloblastoma stem cells, 5 inhibited cell growth, whereas related compound 2 showed high cell differentiation. To the best of our knowledge, 2 and 5 are the first non-nucleoside DNMTi tested in a cancer stem cell line.

  DOI：

  10.1021/jm4012627

文献信息

• Selective Non-nucleoside Inhibitors of Human DNA Methyltransferases Active in Cancer Including in Cancer Stem Cells
  作者：Sergio Valente、Yiwei Liu、Michael Schnekenburger、Clemens Zwergel、Sandro Cosconati、Christina Gros、Maria Tardugno、Donatella Labella、Cristina Florean、Steven Minden、Hideharu Hashimoto、Yanqi Chang、Xing Zhang、Gilbert Kirsch、Ettore Novellino、Paola B. Arimondo、Evelina Miele、Elisabetta Ferretti、Alberto Gulino、Marc Diederich、Xiaodong Cheng、Antonello Mai

  DOI：10.1021/jm4012627

  日期：2014.2.13

  DNA methyltransferases (DNMTs) are important enzymes involved in epigenetic control of gene expression and represent valuable targets in cancer chemotherapy. A number of nucleoside DNMT inhibitors (DNMTi) have been studied in cancer, including in cancer stem cells, and two of them (azacytidine and decitabine) have been approved for treatment of myelodysplastic syndromes. However, only a few non-nucleoside DNMTi have been identified so far, and even fewer have been validated in cancer. Through a process of hit-to-lead optimization, we report here the discovery of compound 5 as a potent non-nucleoside DNMTi that is also selective toward other Ado Met-dependent protein methyltransferases. Compound 5 was potent at single-digit micromolar concentrations against a panel of cancer cells and was less toxic in peripheral blood mononuclear cells than two other compounds tested. In mouse medulloblastoma stem cells, 5 inhibited cell growth, whereas related compound 2 showed high cell differentiation. To the best of our knowledge, 2 and 5 are the first non-nucleoside DNMTi tested in a cancer stem cell line.
• Identification of a novel quinoline-based DNA demethylating compound highly potent in cancer cells
  作者：Clemens Zwergel、Michael Schnekenburger、Federica Sarno、Cecilia Battistelli、Maria Cristina Manara、Giulia Stazi、Roberta Mazzone、Rossella Fioravanti、Christina Gros、Frédéric Ausseil、Cristina Florean、Angela Nebbioso、Raffaele Strippoli、Toshikazu Ushijima、Katia Scotlandi、Marco Tripodi、Paola B. Arimondo、Lucia Altucci、Marc Diederich、Antonello Mai、Sergio Valente

  DOI：10.1186/s13148-019-0663-8

  日期：2019.12

  DNA methyltransferases (DNMTs) are epigenetic enzymes involved in embryonic development, cell differentiation, epithelial to mesenchymal transition, and control of gene expression, whose overexpression or enhanced catalytic activity has been widely reported in cancer initiation and progression. To date, two DNMT inhibitors (DNMTi), 5-azacytidine (5-AZA) and 5-aza-2′-deoxycytidine (DAC), are approved for the treatment of myelodysplastic syndromes and acute myeloid leukemia. Nevertheless, they are chemically instable and quite toxic for healthy cells; thus, the discovery of novel DNMTi is urgent.

  Here, we report the identification of a new quinoline-based molecule, MC3353, as a non-nucleoside inhibitor and downregulator of DNMT. This compound was able, in promoter demethylating assays, to induce enhanced green fluorescence protein (EGFP) gene expression in HCT116 cells and transcription in a cytomegalovirus (CMV) promoter-driven luciferase reporter system in KG-1 cells. Moreover, MC3353 displayed a strong antiproliferative activity when tested on HCT116 colon cancer cells after 48 h of treatment at 0.5 μM. At higher doses, this compound provided a cytotoxic effect in double DNMT knockout HCT116 cells. MC3353 was also screened on a different panel of cancer cells (KG-1 and U-937 acute myeloid leukemia, RAJI Burkitt’s lymphoma, PC-3 prostate cancer, and MDA-MB-231 breast cancer), where it arrested cell proliferation and reduced viability after 48 h of treatment with IC₅₀ values ranging from 0.3 to 0.9 μM. Compared to healthy cell models, MC3353 induced apoptosis (e.g., U-937 and KG-1 cells) or necrosis (e.g., RAJI cells) at lower concentrations. Importantly, together with the main DNMT3A enzyme inhibition, MC3353 was also able to downregulate the DNMT3A protein level in selected HCT116 and PC-3 cell lines. Additionally, this compound provided impairment of the epithelial-to-mesenchymal transition (EMT) by inducing E-cadherin while reducing matrix metalloproteinase (MMP2) mRNA and protein levels in PC-3 and HCT116 cells. Last, tested on a panel of primary osteosarcoma cell lines, MC3353 markedly inhibited cell growth with low single-digit micromolar IC₅₀ ranging from 1.1 to 2.4 μM. Interestingly, in Saos-2 osteosarcoma cells, MC3353 induced both expression of genes and mineralized the matrix as evidence of osteosarcoma to osteoblast differentiation.

  The present work describes MC3353 as a novel DNMTi displaying a stronger in cell demethylating ability than both 5-AZA and DAC, providing re-activation of the silenced ubiquitin C-terminal hydrolase L1 (UCHL1) gene. MC3353 displayed dose- and time-dependent antiproliferative activity in several cancer cell types, inducing cell death and affecting EMT through E-cadherin and MMP2 modulation. In addition, this compound proved efficacy even in primary osteosarcoma cell models, through the modulation of genes involved in osteoblast differentiation.

  摘要： DNA甲基转移酶（DNMTs）是一种表观遗传酶，参与胚胎发育、细胞分化、上皮向间充质转化和基因表达的调控，其过度表达或增强的催化活性已广泛报道与癌症的发生和进展有关。迄今为止，已批准两种DNMT抑制剂（DNMTi），5-氮杂胞苷（5-AZA）和5-氮杂-2'-去氧胞苷（DAC），用于治疗骨髓增生异常综合征和急性髓系白血病。然而，它们在化学上不稳定且对健康细胞有毒性，因此迫切需要发现新的DNMTi。 在这里，我们报告了一种新的喹啉类分子MC3353，作为一种非核苷酸抑制剂和DNMT下调剂，这种化合物能够在启动子去甲基化实验中，诱导HCT116细胞中增强型绿色荧光蛋白（EGFP）基因表达，并在KG-1细胞中的巨细胞病毒（CMV）启动子驱动的荧光素酶报告系统中诱导转录。此外，MC3353在0.5μM的浓度下处理48小时后，在HCT116结肠癌细胞上显示出强烈的抗增殖活性。在较高的剂量下，该化合物在双重DNMT敲除HCT116细胞中产生细胞毒性效应。MC3353还在不同的癌细胞系（KG-1和U-937急性髓系白血病、RAJI Burkitt淋巴瘤、PC-3前列腺癌和MDA-MB-231乳腺癌）上进行筛选，其中在处理48小时后，IC50值范围从0.3到0.9μM，抑制细胞增殖并降低细胞活力。与健康细胞模型相比，MC3353在较低浓度下诱导细胞凋亡（例如U-937和KG-1细胞）或坏死（例如RAJI细胞）。重要的是，除了主要的DNMT3A酶抑制外，MC3353还能够在选定的HCT116和PC-3细胞系中下调DNMT3A蛋白水平。此外，该化合物在PC-3和HCT116细胞中通过诱导E-钙粘蛋白并减少基质金属蛋白酶（MMP2）mRNA和蛋白水平，提供了上皮-间充质转化（EMT）的损害。最后，在一系列原发性骨肉瘤细胞系上进行测试，MC3353明显抑制细胞生长，IC50值范围从1.1到2.4μM。有趣的是，在Saos-2骨肉瘤细胞中，MC3353诱导了基因和矿化基质的表达，作为骨肉瘤向成骨细胞分化的证据。 结论： 本研究描述了MC3353作为一种新的DNMTi，其在细胞去甲基化能力方面比5-AZA和DAC更强，提供了沉默的泛素C端水解酶L1（UCHL1）基因的重新激活。MC3353在多种癌细胞类型中显示出剂量和时间依赖的抗增殖活性，诱导细胞死亡并通过E-钙粘蛋白和MMP2调节影响EMT。此外，该化合物在原发性骨肉瘤细胞模型中也证明了其有效性，通过调节与成骨细胞分化有关的基因。