17-Fluoro-21-methyl-7-phenylmethoxy-3,13-diaza-21-azoniapentacyclo[11.8.0.02,10.04,9.015,20]henicosa-1(21),2(10),4(9),5,7,15(20),16,18-octaen-14-one;chloride | 1394329-17-9

• 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: 17-Fluoro-21-methyl-7-phenylmethoxy-3,13-diaza-21-azoniapentacyclo[11.8.0.02,10.04,9.015,20]henicosa-1(21),2(10),4(9),5,7,15(20),16,18-octaen-14-one;chloride
• 英文别名: 17-fluoro-21-methyl-7-phenylmethoxy-3,13-diaza-21-azoniapentacyclo[11.8.0.02,10.04,9.015,20]henicosa-1(21),2(10),4(9),5,7,15(20),16,18-octaen-14-one;chloride
• CAS: 1394329-17-9
• 化学式: C₂₆H₂₁FN₃O₂*Cl
• 分子量: 461.923
• InChiKey: CJSJBUVLQKRPFE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.25
• 重原子数：
  33
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  48.3
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  17-Fluoro-21-methyl-7-phenylmethoxy-3,13-diaza-21-azoniapentacyclo[11.8.0.02,10.04,9.015,20]henicosa-1(21),2(10),4(9),5,7,15(20),16,18-octaen-14-one;chloride 在 [N-[(1S,2S)-2-(amino-κN)-1,2-diphenylethyl]-4-methylbenzenesulfonamidato-κN]chloro[(1,2, 3,4,5,6-η)-1-methyl-4-(1-methylethyl)benzene]-ruthenium 、 10% Pd/C 、 氢气 作用下， 以 甲酸 、 乙酸乙酯 、 三乙胺 、 N,N-二甲基甲酰胺 为溶剂， 反应 20.0h， 生成 3-fluoro-10-hydroxy evodiamine
  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：

  methyl 5-fluoro-2-(methylamino)benzoate 、 6-(benzyloxy)-2,3,4,9-tetrahydro-1H-β-carbolin-1-one 在 三氯氧磷 作用下， 以 四氢呋喃 为溶剂， 反应 72.67h， 以50%的产率得到17-Fluoro-21-methyl-7-phenylmethoxy-3,13-diaza-21-azoniapentacyclo[11.8.0.02,10.04,9.015,20]henicosa-1(21),2(10),4(9),5,7,15(20),16,18-octaen-14-one;chloride
  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

• 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.