3-amino-10-methoxyevodiamine | 1394329-62-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 3-amino-10-methoxyevodiamine
• 英文别名: 17-Amino-7-methoxy-21-methyl-3,13,21-triazapentacyclo[11.8.0.02,10.04,9.015,20]henicosa-2(10),4(9),5,7,15(20),16,18-heptaen-14-one；17-amino-7-methoxy-21-methyl-3,13,21-triazapentacyclo[11.8.0.02,10.04,9.015,20]henicosa-2(10),4(9),5,7,15(20),16,18-heptaen-14-one
• CAS: 1394329-62-4
• 化学式: C₂₀H₂₀N₄O₂
• 分子量: 348.404
• InChiKey: JBWWYXLPFLMSDT-UHFFFAOYSA-N

物化性质

• 沸点：
  689.8±55.0 °C(Predicted)
• 密度：
  1.43±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  26
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  74.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-amino-10-methoxyevodiamine 在 三溴化硼 作用下， 以 二氯甲烷 为溶剂， 反应 5.0h， 以31%的产率得到3-amino-10-hydroxyevodiamine
  参考文献：
  名称：

  New Tricks for an Old Natural Product: Discovery of Highly Potent Evodiamine Derivatives as Novel Antitumor Agents by Systemic Structure–Activity Relationship Analysis and Biological Evaluations

  摘要：

  Evodiamine is a quinazolinocarboline alkaloid isolated from the fruits of traditional Chinese herb Evodiae fructus. Previously, we identified N13-substituted evodiamine derivatives as potent topoisomerase I inhibitors by structure-based virtual screening and lead optimization. Herein, a library of novel evodiamine derivatives bearing various substitutions or modified scaffold were synthesized. Among them, a number of evodiamine derivatives showed substantial increase of the antitumor activity, with GI(50) values lower than 3 nM. Moreover, these highly potent compounds can effectively induce the apoptosis of A549 cells. Interestingly, further computational target prediction calculations in combination with biological assays confirmed that the evodiamine derivatives acted by dual inhibition of topoisomerases I and II. Moreover, several hydroxyl derivatives, such as 10-hydroxyl evodiamine (10j) and 3-amino-10-hydroxyl evodiamine (18g), also showed good in vivo antitumor efficacy and low toxicity at the dose of 1 mg/kg or 2 mg/kg. They represent promising candidates for the development of novel antitumor agents.

  DOI：

  10.1021/jm300605m
• 作为产物：
  描述：

  N-formyl-5-methoxytryptamine 在 10% Pd/C 、 氢气 、 三氯氧磷 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 24.0h， 生成 3-amino-10-methoxyevodiamine
  参考文献：
  名称：

  New Tricks for an Old Natural Product: Discovery of Highly Potent Evodiamine Derivatives as Novel Antitumor Agents by Systemic Structure–Activity Relationship Analysis and Biological Evaluations

  摘要：

  Evodiamine is a quinazolinocarboline alkaloid isolated from the fruits of traditional Chinese herb Evodiae fructus. Previously, we identified N13-substituted evodiamine derivatives as potent topoisomerase I inhibitors by structure-based virtual screening and lead optimization. Herein, a library of novel evodiamine derivatives bearing various substitutions or modified scaffold were synthesized. Among them, a number of evodiamine derivatives showed substantial increase of the antitumor activity, with GI(50) values lower than 3 nM. Moreover, these highly potent compounds can effectively induce the apoptosis of A549 cells. Interestingly, further computational target prediction calculations in combination with biological assays confirmed that the evodiamine derivatives acted by dual inhibition of topoisomerases I and II. Moreover, several hydroxyl derivatives, such as 10-hydroxyl evodiamine (10j) and 3-amino-10-hydroxyl evodiamine (18g), also showed good in vivo antitumor efficacy and low toxicity at the dose of 1 mg/kg or 2 mg/kg. They represent promising candidates for the development of novel antitumor agents.

  DOI：

  10.1021/jm300605m

文献信息

• Discovery of Novel Multiacting Topoisomerase I/II and Histone Deacetylase Inhibitors
  作者：Shipeng He、Guoqiang Dong、Zhibin Wang、Wei Chen、Yahui Huang、Zhengang Li、Yan Jiang、Na Liu、Jianzhong Yao、Zhenyuan Miao、Wannian Zhang、Chunquan Sheng

  DOI：10.1021/ml500327q

  日期：2015.3.12

  current antitumor drug discovery. Because of the synergistic effect between topoisomerase and HDAC inhibitors, the present study reported the first-in-class triple inhibitors of topoisomerase I/II and HDAC. On the basis of 3-amino-10-hydroxylevodiamine and SAHA, a series of hybrid molecules was successfully designed and synthesized. In particular, compound 8c was proven to be a potent inhibitor of topoisomerase

  设计多靶点药物仍然是当前抗肿瘤药物发现中的重大挑战。由于拓扑异构酶和HDAC抑制剂之间的协同作用，本研究报道了拓扑异构酶I / II和HDAC的同类中的三重抑制剂。在3-氨基-10-羟基乙二胺和SAHA的基础上，成功设计并合成了一系列杂化分子。特别是，化合物8c被证明是拓扑异构酶I / II和HDAC的有效抑制剂，具有良好的抗增殖和凋亡活性。这项概念验证研究还验证了发现三重拓扑异构酶I / II和HDAC抑制剂作为新型抗肿瘤药的有效性。
• Design, Synthesis, and Structure-Activity relationships of Evodiamine-Based topoisomerase (Top)/Histone deacetylase (HDAC) dual inhibitors
  作者：Fugui Zhu、Xiangguo Meng、Huixin Liang、Chunquan Sheng、Guoqiang Dong、Dan Liu、Shanchao Wu

  DOI：10.1016/j.bioorg.2022.105702

  日期：2022.5

  synergistic effect between topoisomerase (Top) and histone deacetylase (HDAC) inhibitors, a series of novel evodiamine-based Top/HDAC dual inhibitors were designed and synthesized. Systematic structure−activity relationship (SAR) studies led to the discovery of compounds 29b and 45b, which simultaneously inhibited Top and HDAC and exhibited potent antitumor activities against the HCT116 cell line.

  在拓扑异构酶（Top）和组蛋白去乙酰化酶（HDAC）抑制剂协同作用的基础上，设计合成了一系列基于吴茱萸碱的新型Top/HDAC双重抑制剂。系统的构效关系 (SAR) 研究导致化合物29b和45b的发现，它们同时抑制 Top 和 HDAC，并对 HCT116 细胞系表现出有效的抗肿瘤活性。化合物29b和45b有效诱导 G2 细胞周期阻滞的细胞凋亡，并显着抑制 HCT116 细胞中的细胞 HDAC，具有良好的体外代谢稳定性。总的来说，这项工作为基于吴茱萸碱的 Top/HDAC 双抑制剂提供了有价值的 SAR 信息和先导化合物。
• 一种吴茱萸碱衍生物及其应用
  申请人：中国人民解放军海军军医大学

  公开号：CN114539267B

  公开（公告）日：2023-04-28
• New Tricks for an Old Natural Product: Discovery of Highly Potent Evodiamine Derivatives as Novel Antitumor Agents by Systemic Structure–Activity Relationship Analysis and Biological Evaluations
  作者：Guoqiang Dong、Shengzheng Wang、Zhenyuan Miao、Jianzhong Yao、Yongqiang Zhang、Zizhao Guo、Wannian Zhang、Chunquan Sheng

  DOI：10.1021/jm300605m

  日期：2012.9.13

  Evodiamine is a quinazolinocarboline alkaloid isolated from the fruits of traditional Chinese herb Evodiae fructus. Previously, we identified N13-substituted evodiamine derivatives as potent topoisomerase I inhibitors by structure-based virtual screening and lead optimization. Herein, a library of novel evodiamine derivatives bearing various substitutions or modified scaffold were synthesized. Among them, a number of evodiamine derivatives showed substantial increase of the antitumor activity, with GI(50) values lower than 3 nM. Moreover, these highly potent compounds can effectively induce the apoptosis of A549 cells. Interestingly, further computational target prediction calculations in combination with biological assays confirmed that the evodiamine derivatives acted by dual inhibition of topoisomerases I and II. Moreover, several hydroxyl derivatives, such as 10-hydroxyl evodiamine (10j) and 3-amino-10-hydroxyl evodiamine (18g), also showed good in vivo antitumor efficacy and low toxicity at the dose of 1 mg/kg or 2 mg/kg. They represent promising candidates for the development of novel antitumor agents.