N-(4-(dimethylamino)benzylidene)-3,4,5-trimethoxyaniline | 387850-52-4

• 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-(dimethylamino)benzylidene)-3,4,5-trimethoxyaniline
• 英文别名: (4-(dimethylamino)benzylidene)-3,4,5-trimethoxyphenylamine
• CAS: 387850-52-4
• 化学式: C₁₈H₂₂N₂O₃
• 分子量: 314.384
• InChiKey: KDPUXTVUKFVKGN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.53
• 重原子数：
  23.0
• 可旋转键数：
  6.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  43.29
• 氢给体数：
  0.0
• 氢受体数：
  5.0

反应信息

• 作为反应物：
  描述：

  N-(4-(dimethylamino)benzylidene)-3,4,5-trimethoxyaniline 在 sodium tetrahydroborate 作用下， 以 甲醇 为溶剂， 生成
  参考文献：
  名称：

  发现新型 3,4-二氢-2(1H)-喹啉酮磺酰胺衍生物作为具有抗癌活性的新型微管蛋白聚合抑制剂

  摘要：

  本文合成了一小部分新型喹啉磺酰胺衍生物，并通过1H NMR和MS对其目标化合物的结构进行了确证。采用MTT法筛选了新靶点化合物对肿瘤细胞系的体外细胞毒活性。其中，化合物 D13 (N-(4-methoxybenzyl)-2-oxo-N-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydroquinoline-6-sulfonamide 对HeLa的增殖（IC50：1.34 μM），该值与该化合物对微管蛋白聚合的抑制活性（IC50：6.74 μM）有很好的相关性。综上所述，发现了一种新型的具有微管蛋白聚合抑制活性的喹啉-磺酰胺衍生物, 可作为先导化合物进行进一步改性。

  DOI：

  10.3390/molecules27051537
• 作为产物：
  描述：

  对二甲氨基苯甲醛 、 3,4,5-三甲氧基苯胺 以 甲醇 为溶剂， 反应 6.0h， 生成 N-(4-(dimethylamino)benzylidene)-3,4,5-trimethoxyaniline
  参考文献：
  名称：

  发现新型 3,4-二氢-2(1H)-喹啉酮磺酰胺衍生物作为具有抗癌活性的新型微管蛋白聚合抑制剂

  摘要：

  本文合成了一小部分新型喹啉磺酰胺衍生物，并通过1H NMR和MS对其目标化合物的结构进行了确证。采用MTT法筛选了新靶点化合物对肿瘤细胞系的体外细胞毒活性。其中，化合物 D13 (N-(4-methoxybenzyl)-2-oxo-N-(3,4,5-trimethoxyphenyl)-1,2,3,4-tetrahydroquinoline-6-sulfonamide 对HeLa的增殖（IC50：1.34 μM），该值与该化合物对微管蛋白聚合的抑制活性（IC50：6.74 μM）有很好的相关性。综上所述，发现了一种新型的具有微管蛋白聚合抑制活性的喹啉-磺酰胺衍生物, 可作为先导化合物进行进一步改性。

  DOI：

  10.3390/molecules27051537

文献信息

• 3-Vinylazetidin-2-Ones: Synthesis, Antiproliferative and Tubulin Destabilizing Activity in MCF-7 and MDA-MB-231 Breast Cancer Cells
  作者：Wang、Malebari、Greene、O’Boyle、Fayne、Nathwani、Twamley、McCabe、Keely、Zisterer、Meegan

  DOI：10.3390/ph12020056

  日期：——

  Microtubule-targeted drugs are essential chemotherapeutic agents for various types of cancer. A series of 3-vinyl-β-lactams (2-azetidinones) were designed, synthesized and evaluated as potential tubulin polymerization inhibitors, and for their antiproliferative effects in breast cancer cells. These compounds showed potent activity in MCF-7 breast cancer cells with an IC50 value of 8 nM for compound 7s 4-[3-Hydroxy-4-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-3-vinylazetidin-2-one) which was comparable to the activity of Combretastatin A-4. Compound 7s had minimal cytotoxicity against both non-tumorigenic HEK-293T cells and murine mammary epithelial cells. The compounds inhibited the polymerisation of tubulin in vitro with an 8.7-fold reduction in tubulin polymerization at 10 M for compound 7s and were shown to interact at the colchicine-binding site on tubulin, resulting in significant G2/M phase cell cycle arrest. Immunofluorescence staining of MCF-7 cells confirmed that β-lactam 7s is targeting tubulin and resulted in mitotic catastrophe. A docking simulation indicated potential binding conformations for the 3-vinyl-β-lactam 7s in the colchicine domain of tubulin. These compounds are promising candidates for development as antiproiferative microtubule-disrupting agents.

  微管靶向药物是各种癌症的重要化疗药物。一系列3-乙烯基-β-内酰胺（2-氮杂环丙酮）被设计、合成并评估为潜在的微管聚合抑制剂，以及它们在乳腺癌细胞中的抗增殖效应。这些化合物在MCF-7乳腺癌细胞中表现出强大的活性，其中化合物7s（4-[3-羟基-4-甲氧基苯基]-1-(3,4,5-三甲氧基苯基)-3-乙烯基氮杂环丙酮）的IC50值为8 nM，与康布雷他定A-4的活性相当。化合物7s对非肿瘤性HEK-293T细胞和小鼠乳腺上皮细胞均具有最小的细胞毒性。这些化合物在体外抑制了微管的聚合，在10 μM的浓度下，化合物7s使微管聚合减少了8.7倍，并且显示出它们与微管上的秋水仙碱结合位点相互作用，导致显著的G2/M期细胞周期阻滞。MCF-7细胞的免疫荧光染色证实了β-内酰胺7s靶向微管，并导致有丝分裂灾难。对于3-乙烯基-β-内酰胺7s在微管秋水仙碱结合区域的潜在结合构象进行的对接模拟表明了潜在的结合构象。这些化合物是作为抗增殖微管破坏剂的发展有前途的候选药物。
• Antiproliferative and Tubulin-Destabilising Effects of 3-(Prop-1-en-2-yl)azetidin-2-Ones and Related Compounds in MCF-7 and MDA-MB-231 Breast Cancer Cells
  作者：Shu Wang、Azizah M. Malebari、Thomas F. Greene、Shubhangi Kandwal、Darren Fayne、Seema M. Nathwani、Daniela M. Zisterer、Brendan Twamley、Niamh M O’Boyle、Mary J. Meegan

  DOI：10.3390/ph16071000

  日期：——

  (2-azetidinone) scaffold. These compounds, together with related prodrugs, were evaluated for their antiproliferative activity, cell cycle effects and ability to inhibit tubulin assembly. The compounds demonstrated significant in vitro antiproliferative activities in MCF-7 breast cancer cells, particularly for compounds 9h, 9q, 9r, 10p, 10r and 11h, with IC50 values in the range 10–33 nM. These compounds were

  一系列新型3-(prop-1-en-2-yl)azetidin-2-one、3-allylazetidin-2-one和3-(buta-1,3-dien-1-yl)azetidin-2-设计并合成了考布他汀 A-4 (CA-4) 的一种类似物作为秋水仙碱结合位点抑制剂 (CBSI)，其中 CA-4 的乙烯桥被 β-内酰胺 (2-氮杂环丁酮) 支架取代。对这些化合物以及相关前药的抗增殖活性、细胞周期效应和抑制微管蛋白组装的能力进行了评估。这些化合物在 MCF-7 乳腺癌细胞中表现出显着的体外抗增殖活性，特别是化合物 9h、9q、9r、10p、10r 和 11h，IC50 值在 10-33 nM 范围内。这些化合物在三阴性乳腺癌 (TBNC) 细胞系 MDA-MB-231 中也有效，IC50 值在 23-33 nM 范围内，并且与 CA-4 的活性相当。这些化合物在体外抑制微管蛋白的聚合，显着
• Synthesis and Biochemical Evaluation of 3-Phenoxy-1,4-diarylazetidin-2-ones as Tubulin-Targeting Antitumor Agents
  作者：Thomas F. Greene、Shu Wang、Lisa M. Greene、Seema M. Nathwani、Jade K. Pollock、Azizah M. Malebari、Thomas McCabe、Brendan Twamley、Niamh M. O’Boyle、Daniela M. Zisterer、Mary J. Meegan

  DOI：10.1021/acs.jmedchem.5b01086

  日期：2016.1.14

  Structure-activity relationships for a series of 3-phenoxy-1,4-diarylazetidin-2-ones were investigated, leading to the discovery of a number of potent antiproliferative compounds, including trans-4-(3-hydroxy-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (78b) and trans-4-(3-amino-4-methoxyphenyl)-3-phenoxy-1-(3,4,5-trimethoxyphenyl)azetidin-2-one (90b). X-ray crystallography studies indicate the potential importance of the torsional angle between the 1-phenyl A ring and 4-phenyl B ring for potent antiproliferative activity and that a trans configuration between the 3-phenoxy and 4-phenyl rings is generally optimal. These compounds displayed IC50 values of 38 and 19 nM, respectively, in MCF-7 breast cancer cells, inhibited the polymerization of isolated tubulin in vitro, disrupted the microtubular structure in MCF-7 cells as visualized by confocal microscopy, and caused G(2)/M arrest and apoptosis. Compound 90b possessed a mean GI50 value of 22 nM in the NCI60 cell line screen, displayed minimal cytotoxicity, and was shown to interact at the colchicine-binding site on beta-tubulin. Phosphate and amino acid prodrugs of both 78b and 90b were synthesized, of which the alanine amide 102b retained potency and is a promising candidate for further clinical development.
• Synthesis, biochemical and molecular modelling studies of antiproliferative azetidinones causing microtubule disruption and mitotic catastrophe
  作者：Niamh M. O’Boyle、Miriam Carr、Lisa M. Greene、Niall O. Keely、Andrew J.S. Knox、Thomas McCabe、David G. Lloyd、Daniela M. Zisterer、Mary J. Meegan

  DOI：10.1016/j.ejmech.2011.07.039

  日期：2011.9

  The structure-activity relationships of antiproliferative beta-lactams, focusing on modifications at the 4-position of the beta-lactam ring, is described. Synthesis of this series of compounds was achieved utilizing the Staudinger and Reformatsky reactions. The antiproliferative activity was assessed in MCF-7 cells, where the 4-(4-ethoxy)phenyl substituted compound 26 displayed the most potent activity with an IC(50) value of 0.22 mu M. The mechanism of action was demonstrated to be by inhibition of tubulin polymerisation. Cell exposure to combretastatin A-4 and 26 led to arrest of MCF-7 cells in the G2/M phase of the cell cycle and induction of apoptosis. Additionally, mitotic catastrophe for combretastatin A-4 and for 26 was demonstrated in breast cancer cells for the first time, as evidenced by the formation of giant, multinucleated cells. (C) 2011 Elsevier Masson SAS. All rights reserved.