2,4-dichloro-6-methoxy-7-[3-(piperidin-1-yl)propoxy]quinazoline | 1350755-41-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 2,4-dichloro-6-methoxy-7-[3-(piperidin-1-yl)propoxy]quinazoline
• 英文别名: 2,4-Dichloro-6-methoxy-7-[3-(piperidin-1-yl)propoxy]quinazoline；2,4-dichloro-6-methoxy-7-(3-piperidin-1-ylpropoxy)quinazoline
• CAS: 1350755-41-7
• 化学式: C₁₇H₂₁Cl₂N₃O₂
• 分子量: 370.279
• InChiKey: LWPFLMBUTXWJSW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  24
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  47.5
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2,4-dichloro-6-methoxy-7-[3-(piperidin-1-yl)propoxy]quinazoline 在 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 异丙醇 为溶剂， 反应 0.25h， 生成 2-(azepan-1-yl)-N-(1-isopropylpiperidin-4-yl)-6-methoxy-7-(3-(piperidin-1-yl)propoxy)quinazolin-4-amine
  参考文献：
  名称：

  Optimization of Cellular Activity of G9a Inhibitors 7-Aminoalkoxy-quinazolines

  摘要：

  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.

  DOI：

  10.1021/jm200903z
• 作为产物：
  描述：

  苯甲酸,4-(3-氯丙氧基)-3-甲氧基-,甲基酯 在 ammonium acetate 、 水 、 硝酸 、 乙酸酐 、 四丁基碘化铵 、 铁粉 、 potassium carbonate 、 溶剂黄146 、 N,N-二乙基苯胺 、 sodium iodide 、 sodium hydroxide 、 三氯氧磷 作用下， 以 甲醇 、 水 、 乙酸乙酯 、 乙腈 为溶剂， 反应 10.0h， 生成 2,4-dichloro-6-methoxy-7-[3-(piperidin-1-yl)propoxy]quinazoline
  参考文献：
  名称：

  Optimization of Cellular Activity of G9a Inhibitors 7-Aminoalkoxy-quinazolines

  摘要：

  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.

  DOI：

  10.1021/jm200903z

文献信息

• [EN] HETEROCHROMATIN GENE REPRESSION INHIBITORS<br/>[FR] INHIBITEURS DE RÉPRESSION DE GÈNE D'HÉTÉROCHROMATINE
  申请人：UNIV NORTH CAROLINA CHAPEL HILL

  公开号：WO2019006322A1

  公开（公告）日：2019-01-03

  The present disclosure relates to chemical compounds that inhibit HP1-mediated heterochromatin formation, pharmaceutical compositions containing such compounds, methods of identifying such compounds, and their use in the treatment of disorders related to heterochromatin formation such as, for example, a disorder of cellular proliferation (e.g., cancer). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  本公开涉及抑制HP1介导的异染色质形成的化合物、含有这些化合物的药物组合物、识别这些化合物的方法，以及它们在治疗与异染色质形成相关的疾病中的用途，例如细胞增殖障碍（例如癌症）。本摘要旨在作为在特定领域搜索的扫描工具，不打算限制本发明。
• 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。
• Heterochromatin gene repression inhibitors
  申请人：The University of North Carolina at Chapel Hill

  公开号：US11254654B2

  公开（公告）日：2022-02-22

  The present disclosure relates to chemical compounds that inhibit HP1-mediated heterochromatin formation, pharmaceutical compositions containing such compounds, methods of identifying such compounds, and their use in the treatment of disorders related to heterochromatin formation such as, for example, a disorder of cellular proliferation (e.g., cancer). This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  本公开涉及抑制HP1介导的异染色质形成的化学化合物、含有此类化合物的药物组合物、鉴定此类化合物的方法，以及它们在治疗与异染色质形成有关的疾病（例如细胞增殖障碍（如癌症））中的用途。本摘要旨在作为在特定技术领域进行搜索的扫描工具，并非对本发明的限制。
• HETEROCHROMATIN GENE REPRESSION INHIBITORS
  申请人：The University of North Carolina at Chapel Hill

  公开号：EP3645006A1

  公开（公告）日：2020-05-06