2,7-Dihydroxy-9-chloroacridine | 156644-26-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 2,7-Dihydroxy-9-chloroacridine
• 英文别名: 9-Chloro-2,7-acridinediol；9-chloroacridine-2,7-diol
• CAS: 156644-26-7
• 化学式: C₁₃H₈ClNO₂
• 分子量: 245.665
• InChiKey: QVDLIQJOIWLMEO-UHFFFAOYSA-N

物化性质

• 沸点：
  469.0±25.0 °C(predicted)
• 密度：
  1.538±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  17
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  53.4
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2,7-Dihydroxy-9-chloroacridine 在 tetraphosphorus decasulfide 作用下， 以 N,N-二甲基丙烯基脲 为溶剂， 生成 2,7-dihydroxy-10H-acridine-9-thione
  参考文献：
  名称：

  Structure–activity relationship study of acridine analogs as haspin and DYRK2 kinase inhibitors

  摘要：

  Haspin is a serine/threonine kinase required for completion of normal mitosis that is highly expressed during cell proliferation, including in a number of neoplasms. Consequently, it has emerged as a potential therapeutic target in oncology. A high throughput screen of approximately 140,000 compounds identified an acridine analog as a potent haspin kinase inhibitor. Profiling against a panel of 270 kinases revealed that the compound also exhibited potent inhibitory activity for DYRK2, another serine/threonine kinase. An optimization study of the acridine series revealed that the structure-activity relationship (SAR) of the acridine series for haspin and DYRK2 inhibition had many similarities. However, several structural differences were noted that allowed generation of a potent haspin kinase inhibitor (33, IC(50) <60 nM) with 180fold selectivity over DYRK2. In addition, a moderately potent DYRK2 inhibitor (41, IC(50) <400 nM) with a 5.4-fold selectivity over haspin was also identified. (C) 2010 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2010.04.150
• 作为产物：
  描述：

  9-氯-2,7-二甲氧基吖啶 在 氢溴酸 作用下， 反应 17.0h， 以90%的产率得到2,7-Dihydroxy-9-chloroacridine
  参考文献：
  名称：

  Crown Ethers Derived from 2,7-Dihydroxyacridine and 2,7-Dihydroxyacridan-9-one

  摘要：

  We report the synthesis of nine acridine crown ethers 11a, 11b, 12a, 12b, 13a, 13b, 14b, 15b, and 16b having one or two acridine rings linked by poly(ethylene glycol) chains. Their H-1 and C-13 NMR spectra have been analyzed and the chemical shifts related to conformational aspects of the chain and to the tautomerism of the acridan-9-one ring. The transport rates have been determined for compounds 11b and 12b against a large variety of ions. While compound 11b is devoid of complexing properties, compound 12b transports Fe2+, Cu+, and Ag+ but not alkali-metal cations.

  DOI：

  10.1021/jo00097a016

文献信息

• 一种抗肿瘤化合物及其合成方法与应用
  申请人：北京大学

  公开号：CN110981803B

  公开（公告）日：2021-04-13

  本发明属于药物化学领域，具体涉及一种抗肿瘤化合物及其合成方法与应用。所述化合物具有通式I或通式II所示结构，对蛋白酶体调节激酶DYRK2展现出很好的抑制活性，进而可以通过抑制蛋白酶体达成抗肿瘤活性。本发明还涉及所述化合物的合成方法，该方法采用化学全合成路线，这种汇聚式的合成路线可应用于类似结构化合物及相关衍生物的化学合成，为新型抗肿瘤药物开辟了广阔发展空间。
• Selective inhibition reveals the regulatory function of DYRK2 in protein synthesis and calcium entry
  作者：Tiantian Wei、Jue Wang、Ruqi Liang、Wendong Chen、Yilan Chen、Mingzhe Ma、An He、Yifei Du、Wenjing Zhou、Zhiying Zhang、Xin Zeng、Chu Wang、Jin Lu、Xing Guo、Xiao-Wei Chen、Youjun Wang、Ruijun Tian、Junyu Xiao、Xiaoguang Lei

  DOI：10.7554/elife.77696

  日期：——

  The dual-specificity tyrosine phosphorylation-regulated kinase DYRK2 has emerged as a critical regulator of cellular processes. We took a chemical biology approach to gain further insights into its function. We developed C17, a potent small-molecule DYRK2 inhibitor, through multiple rounds of structure-based optimization guided by several co-crystallized structures. C17 displayed an effect on DYRK2 at a single-digit nanomolar IC₅₀ and showed outstanding selectivity for the human kinome containing 467 other human kinases. Using C17 as a chemical probe, we further performed quantitative phosphoproteomic assays and identified several novel DYRK2 targets, including eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1) and stromal interaction molecule 1 (STIM1). DYRK2 phosphorylated 4E-BP1 at multiple sites, and the combined treatment of C17 with AKT and MEK inhibitors showed synergistic 4E-BP1 phosphorylation suppression. The phosphorylation of STIM1 by DYRK2 substantially increased the interaction of STIM1 with the ORAI1 channel, and C17 impeded the store-operated calcium entry process. These studies collectively further expand our understanding of DYRK2 and provide a valuable tool to pinpoint its biological function.

  双特异性酪氨酸磷酸化调控激酶 DYRK2 已成为细胞过程的关键调控因子。我们采用化学生物学方法来进一步了解它的功能。在多个共晶体结构的指导下，我们通过多轮基于结构的优化，开发出了一种强效的小分子 DYRK2 抑制剂 C17。C17 对 DYRK2 的作用 IC50 为个位数纳摩尔，并且对包含 467 种其他人类激酶的人类激酶组显示出卓越的选择性。利用 C17 作为化学探针，我们进一步进行了定量磷酸化蛋白组测定，并确定了几个新的 DYRK2 靶点，包括真核翻译起始因子 4E 结合蛋白 1（4E-BP1）和基质相互作用分子 1（STIM1）。DYRK2 在多个位点使 4E-BP1 磷酸化，用 AKT 和 MEK 抑制剂联合处理 C17 会协同抑制 4E-BP1 磷酸化。DYRK2 对 STIM1 的磷酸化大大增加了 STIM1 与 ORAI1 通道的相互作用，而 C17 则阻碍了贮存操作的钙离子进入过程。这些研究共同进一步拓展了我们对 DYRK2 的认识，并为明确其生物学功能提供了宝贵的工具。
• Structure–activity relationship study of acridine analogs as haspin and DYRK2 kinase inhibitors
  作者：Gregory D. Cuny、Maxime Robin、Natalia P. Ulyanova、Debasis Patnaik、Valerie Pique、Gilles Casano、Ji-Feng Liu、Xiangjie Lin、Jun Xian、Marcie A. Glicksman、Ross L. Stein、Jonathan M.G. Higgins

  DOI：10.1016/j.bmcl.2010.04.150

  日期：2010.6

  Haspin is a serine/threonine kinase required for completion of normal mitosis that is highly expressed during cell proliferation, including in a number of neoplasms. Consequently, it has emerged as a potential therapeutic target in oncology. A high throughput screen of approximately 140,000 compounds identified an acridine analog as a potent haspin kinase inhibitor. Profiling against a panel of 270 kinases revealed that the compound also exhibited potent inhibitory activity for DYRK2, another serine/threonine kinase. An optimization study of the acridine series revealed that the structure-activity relationship (SAR) of the acridine series for haspin and DYRK2 inhibition had many similarities. However, several structural differences were noted that allowed generation of a potent haspin kinase inhibitor (33, IC(50) <60 nM) with 180fold selectivity over DYRK2. In addition, a moderately potent DYRK2 inhibitor (41, IC(50) <400 nM) with a 5.4-fold selectivity over haspin was also identified. (C) 2010 Elsevier Ltd. All rights reserved.
• Crown Ethers Derived from 2,7-Dihydroxyacridine and 2,7-Dihydroxyacridan-9-one
  作者：Alain Vichet、Anne-Marie Patellis、Jean-Pierre Galy、Anne-Marie Galy、Jacques Barbe、Jose Elguero

  DOI：10.1021/jo00097a016

  日期：1994.9

  We report the synthesis of nine acridine crown ethers 11a, 11b, 12a, 12b, 13a, 13b, 14b, 15b, and 16b having one or two acridine rings linked by poly(ethylene glycol) chains. Their H-1 and C-13 NMR spectra have been analyzed and the chemical shifts related to conformational aspects of the chain and to the tautomerism of the acridan-9-one ring. The transport rates have been determined for compounds 11b and 12b against a large variety of ions. While compound 11b is devoid of complexing properties, compound 12b transports Fe2+, Cu+, and Ag+ but not alkali-metal cations.