methyl 5-methoxy-2-nitro-4-(3-(piperidin-1-yl)propoxy)benzoate | 927173-22-6

• 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: methyl 5-methoxy-2-nitro-4-(3-(piperidin-1-yl)propoxy)benzoate
• 英文别名: Methyl 5-methoxy-2-nitro-4-[3-(piperidin-1-YL)propoxy]benzoate；methyl 5-methoxy-2-nitro-4-(3-piperidin-1-ylpropoxy)benzoate
• CAS: 927173-22-6
• 化学式: C₁₇H₂₄N₂O₆
• 分子量: 352.387
• InChiKey: QVYVTFXYZAPKSG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  25
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  93.8
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  methyl 5-methoxy-2-nitro-4-(3-(piperidin-1-yl)propoxy)benzoate 在 四丁基溴化铵 、 氢气 、 甲酸铵 、 sodium hydroxide 、 三氯氧磷 作用下， 以 甲醇 、 二氯甲烷 、 丁酮 为溶剂， 反应 49.0h， 生成 N-(3-bromophenyl)-N'-{4-[(6-methoxy-7-piperidinopropoxyquinazolin-4-yl)oxy]-phenyl}urea
  参考文献：
  名称：

  Inhibition of tumor cell growth and angiogenesis by 7-Aminoalkoxy-4-aryloxy-quinazoline ureas, a novel series of multi-tyrosine kinase inhibitors

  摘要：

  Several regulatory and signaling molecules governing angiogenesis are targets of interest for the development of drugs in the cancer, including growth factors such as Vascular Endothelial Growth Factor (VEGF) and Platelet-Derived Growth Factor (PDGF). A series of 4-aryloxy-6,7-dimethoxyquinazolines, previously synthesized in our laboratory, has shown a nanomolar inhibition of kinase enzymatic activity of VEGFR, PDGFR and c-Kit. We have therefore studied the impact of the variation in the 7-position substitution of the quinazoline core. Substitution by aminoalkoxy chains led to new highly potent ATP-competitive inhibitors of VEGFR, PDGFR and c-Kit enzyme with IC50 values in the nanomolar range and this substitution has increased greatly antiproliferative activity on cancer cell lines (PC3, MCF7, HT29) and HUVEC (human umbilical vein endothelial cells). One of the most promising compounds (36) was assessed for its ability to limit the induction of web like network of capillary tubes by the human umbilical vascular endothelial cells (HUVEC) and for its ability to inhibit invasion. (C) 2014 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2014.04.007
• 作为产物：
  描述：

  香草酸甲酯 在 硝酸 、 四丁基碘化铵 、 potassium carbonate 、 溶剂黄146 、 sodium iodide 作用下， 以 丙酮 、 乙腈 为溶剂， 反应 8.0h， 生成 methyl 5-methoxy-2-nitro-4-(3-(piperidin-1-yl)propoxy)benzoate
  参考文献：
  名称：

  改进了取代 6,7-二羟基-4-喹唑啉胺的合成：坦度替尼、厄洛替尼和吉非替尼。

  摘要：

  报道了三种取代的 6,7-二羟基-4-喹唑啉胺的合成：坦杜替尼 (1)、厄洛替尼 (2) 和吉非替尼 (3)，产量提高。中间体通过NMR表征并且通过HPLC确定纯度。

  DOI：

  10.3390/11040286

文献信息

• Synthesis and antitumor activity evaluation of quinazoline derivatives bearing piperazine-1-carbodithioate moiety at C4-position
  作者：Ying Zhang、Chao-Rui Yang、Xue Tang、Sheng-Li Cao、Ting-Ting Ren、Man Gao、Ji Liao、Xingzhi Xu

  DOI：10.1016/j.bmcl.2016.08.060

  日期：2016.10

  A series of quinazoline derivatives bearing piperazine-1-carbodithioate moiety at the C4-position were synthesized using piperidine and 1-bromo-3-chloropropane as starting materials via eight steps. Final compounds 8a-q and 9a-i were evaluated for their antiproliferative activity against human lung cancer A549, breast adenocarcinoma MCF-7, and colorectal cancer HCT-116 cell lines. The results showed

  以哌啶和1-溴-3-氯丙烷为原料，经八个步骤合成了一系列在C4位带有哌嗪-1-碳二硫代酸酯部分的喹唑啉衍生物。评估了最终化合物8a-q和9a-i对人肺癌A549，乳腺癌MCF-7和结肠直肠癌HCT-116细胞系的抗增殖活性。结果表明，在26种最终化合物中，有14种抑制了三种癌细胞系的增殖，IC50值均小于10μM。当用代表性化合物8n处理时，HCT-116细胞停滞在细胞周期的G0 / G1期。这为进一步研究作用机理提供了线索。
• Improved Synthesis of Substituted 6,7-Dihydroxy-4-quinazolineamines: Tandutinib, Erlotinib and Gefitinib
  作者：Petr Knesl、Dirk Röseling、Ulrich Jordis

  DOI：10.3390/11040286

  日期：——

  The synthesis of three substituted 6,7-dihydroxy-4-quinazolineamines: tandutinib (1), erlotinib (2) and gefitinib (3) in improved yields is reported. The intermediates were characterized by NMR and the purities determined by HPLC.

  报道了三种取代的 6,7-二羟基-4-喹唑啉胺的合成：坦杜替尼 (1)、厄洛替尼 (2) 和吉非替尼 (3)，产量提高。中间体通过NMR表征并且通过HPLC确定纯度。
• MS0621, a novel small-molecule modulator of Ewing sarcoma chromatin accessibility, interacts with an RNA-associated macromolecular complex and influences RNA splicing
  作者：Tamara Vital、Aminah Wali、Kyle V. Butler、Yan Xiong、Joseph P. Foster、Shelsa S. Marcel、Andrew W. McFadden、Valerie U. Nguyen、Benton M. Bailey、Kelsey N. Lamb、Lindsey I. James、Stephen V. Frye、Amber L. Mosely、Jian Jin、Samantha G. Pattenden、Ian J. Davis

  DOI：10.3389/fonc.2023.1099550

  日期：——

  Ewing sarcoma is a cancer of children and young adults characterized by the critical translocation-associated fusion oncoprotein EWSR1::FLI1. EWSR1::FLI1 targets characteristic genetic loci where it mediates aberrant chromatin and the establishment of de novo enhancers. Ewing sarcoma thus provides a model to interrogate mechanisms underlying chromatin dysregulation in tumorigenesis. Previously, we developed a high-throughput chromatin-based screening platform based on the de novo enhancers and demonstrated its utility in identifying small molecules capable of altering chromatin accessibility. Here, we report the identification of MS0621, a molecule with previously uncharacterized mechanism of action, as a small molecule modulator of chromatin state at sites of aberrant chromatin accessibility at EWSR1::FLI1-bound loci. MS0621 suppresses cellular proliferation of Ewing sarcoma cell lines by cell cycle arrest. Proteomic studies demonstrate that MS0621 associates with EWSR1::FLI1, RNA binding and splicing proteins, as well as chromatin regulatory proteins. Surprisingly, interactions with chromatin and many RNA-binding proteins, including EWSR1::FLI1 and its known interactors, were RNA-independent. Our findings suggest that MS0621 affects EWSR1::FLI1-mediated chromatin activity by interacting with and altering the activity of RNA splicing machinery and chromatin modulating factors. Genetic modulation of these proteins similarly inhibits proliferation and alters chromatin in Ewing sarcoma cells. The use of an oncogene-associated chromatin signature as a target allows for a direct approach to screen for unrecognized modulators of epigenetic machinery and provides a framework for using chromatin-based assays for future therapeutic discovery efforts.

  尤文肉瘤是一种儿童和青少年癌症，其特征是与关键易位相关的融合肿瘤蛋白 EWSR1::FLI1。EWSR1::FLI1以特征性遗传位点为靶点，在这些位点上介导异常染色质和新生增强子的建立。因此，尤文肉瘤为研究肿瘤发生过程中染色质失调的机制提供了一个模型。在此之前，我们基于新生增强子开发了一种基于染色质的高通量筛选平台，并证明了它在鉴定能够改变染色质可及性的小分子方面的实用性。在这里，我们报告了 MS0621 的鉴定结果，这是一种具有之前未表征的作用机制的分子，是 EWSR1::FLI1 结合位点染色质可及性异常位点染色质状态的小分子调节剂。MS0621 通过抑制细胞周期来抑制尤文肉瘤细胞系的细胞增殖。蛋白质组学研究表明，MS0621 能与 EWSR1::FLI1、RNA 结合蛋白、剪接蛋白以及染色质调控蛋白结合。令人惊讶的是，MS0621与染色质和许多RNA结合蛋白（包括EWSR1::FLI1及其已知的相互作用因子）的相互作用与RNA无关。我们的研究结果表明，MS0621通过与RNA剪接机制和染色质调节因子相互作用并改变其活性，从而影响EWSR1::FLI1介导的染色质活性。对这些蛋白的基因调控同样会抑制尤文肉瘤细胞的增殖并改变其染色质。使用癌基因相关染色质特征作为靶标，可以直接筛选出尚未认识到的表观遗传机制调节因子，并为未来使用基于染色质的检测方法发现治疗方法提供了一个框架。
• Optimization of Cellular Activity of G9a Inhibitors 7-Aminoalkoxy-quinazolines
  作者：Feng Liu、Dalia Barsyte-Lovejoy、Abdellah Allali-Hassani、Yunlong He、J. Martin Herold、Xin Chen、Christopher M. Yates、Stephen V. Frye、Peter J. Brown、Jing Huang、Masoud Vedadi、Cheryl H. Arrowsmith、Jian Jin

  DOI：10.1021/jm200903z

  日期：2011.9.8

  Protein lysine methyltransferase G9a plays key roles in the transcriptional repression of a variety of genes via dimethylation of lysine 9 on histone H3 (H3K9me2) of chromatin as well as dimethylation of nonhistone proteins including tumor suppressor p53. We previously reported the discovery of UNC0321 (3), the most potent G9a inhibitor to date, via structure-based design and structure-activity relationship (SAR) exploration of the quinazoline scaffold represented by BIX01294 (1). Despite its very high in vitro potency, compound 3 lacks sufficient cellular potency. The design and synthesis of several generations of new analogues aimed at improving cell membrane permeability while maintaining high in vitro potency resulted in the discovery of a number of novel G9a inhibitors such as UNC0646 (6) and UNC0631 (7) with excellent potency in a variety of cell lines and excellent separation of functional potency versus cell toxicity. The design, synthesis, and cellular SAR of these potent G9a inhibitors are described.
• Molecules 2006, 11, 286-297
  作者：

  DOI：——

  日期：——