(6,9-二甲基-吩嗪-1-基)-咪唑-1-基-甲酮 | 1026959-16-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 中文名称: (6,9-二甲基-吩嗪-1-基)-咪唑-1-基-甲酮
• 英文名称: (6,9-Dimethylphenazin-1-yl)-imidazol-1-ylmethanone
• CAS: 1026959-16-9
• 化学式: C₁₈H₁₄N₄O
• 分子量: 302.335
• InChiKey: RTAFPNZPDSYLKC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  23
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.11
• 拓扑面积：
  60.7
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  三乙烯四胺 、 (6,9-二甲基-吩嗪-1-基)-咪唑-1-基-甲酮 以 四氢呋喃 为溶剂， 生成 N-[2-[2-[2-[(6,9-dimethylphenazine-1-carbonyl)amino]ethylamino]ethylamino]ethyl]-6,9-dimethylphenazine-1-carboxamide
  参考文献：
  名称：

  阳离子双（9-甲基吩嗪-1-羧酰胺）：一系列有效的拓扑异构酶靶向抗癌药物的生物学活性和接头链结构之间的关系。

  摘要：

  双（9-甲基吩嗪-1-羧酰胺）通过各种不同的dicicic（CH（2））（n）（）NR（CH（2））（m）NR（CH（2））（n）接头连接通过使9-甲基吩嗪-1-羧酸咪唑啉化物与适当的多胺反应，制备了长度（羧酰胺NN距离为11.0至18.4A）和刚性。评价了这些化合物在P388白血病，Lewis肺癌以及野生型（JL（C））和突变型（JL（A）和JL（D））形式的人Jurkat白血病中具有低水平的拓扑异构酶II的生长抑制特性（拓扑II）。这些化合物在抗性Jurkat品系中均具有小于1的IC（50）比，这与对topo II的抑制作用不是主要的作用机理相一致。由（CH（2））（2）NR（CH（2））（2）NR（CH（2））（2）接头连接的类似物是非常有效的细胞毒素，对人类细胞系具有选择性，但是绝对效能从R = H到R = Me急剧下降到R = Pr和Bu。相反，（CH（2））（2）NR（CH（2

  DOI：

  10.1021/jm0003283
• 作为产物：
  描述：

  2,5-二甲基苯胺 在 铜 、 copper(l) chloride N-乙基吗啉 、 sodium ethanolate 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 26.5h， 生成 (6,9-二甲基-吩嗪-1-基)-咪唑-1-基-甲酮
  参考文献：
  名称：

  Bis(phenazine-1-carboxamides):  Structure−Activity Relationships for a New Class of Dual Topoisomerase I/II-Directed Anticancer Drugs

  摘要：

  Ring-substituted bis(phenazine-1-carboxamides), linked by a -(CH2)(3)NMe(CH2)(3)- chain, were prepared from the corresponding substituted phenazine-1-carboxylic acids by reaction of the intermediate imidazolides with bis(3-aminopropyl)methylamine. The compounds were evaluated for growth inhibitory activity in a panel of tumor cell lines, including P388 leukemia, Lewis lung carcinoma, and wild-type (JL(C)) and mutant (JL(A) and JL(D)) forms of human Jurkat leukemia; The latter mutant lines are resistant to topoisomerase (topo) II targeted agents because of lower levels of the enzyme. Analogues with small, lipophilic substituents (e.g,, Me, Cl) at the 9-position were the most potent inhibitors, superior to the corresponding dimeric bis(acridine-4-carboxamides) (bis-DACA analogues). Several of the compounds were preferentially (up to 2-fold) more cytotoxic toward the mutant Jurkat lines than the wild-type. To test whether this selectivity was related to topoisomerase action, the most potent of the compounds (9-methyl) was evaluated in a cell-free system. It poisoned topo I at drug concentrations of 0.25 and 0.5 mu M and inhibited the catalytic activity of both topo I and topo II at concentrations of 1 and 5 mu M, respectively. Results from the NCI human tumor cell line panel showed the compounds had preferential activity toward colon tumor lines ton average 9.5-fold more active in the HT29 line than in the cell line, panel as a whole). Several analogues produced significant growth delays in the relatively refractory subcutaneous colon 38 tumor model in vivo. In particular, the 9-methyl compound was substantially more potent in this tumor model than the clinical dual topo I/II poison DACA (total dose 90 versus 400 mg/kg) with comparable activity. The bis(phenazine-1-carboxamides) are a new and interesting class of dual topo I/II-directed anticancer drugs.

  DOI：

  10.1021/jm990423f

文献信息

• Dicationic Bis(9-methylphenazine-1-carboxamides):  Relationships between Biological Activity and Linker Chain Structure for a Series of Potent Topoisomerase Targeted Anticancer Drugs
  作者：Swarna A. Gamage、Julie A. Spicer、Graeme J. Finlay、Alistair J. Stewart、Peter Charlton、Bruce C. Baguley、William A. Denny

  DOI：10.1021/jm0003283

  日期：2001.4.1

  reverse effects, with the R = Me analogue being more potent than the R = H one as well as being the most potent in the series [IC(50) in JL(C) cells 0.08 nM; superior to that for the clinical bis(naphthalimide) LU 79553]. Overall, the IC(50)s of analogues with linker chains (CH(2))(n)NH(CH(2))(m)NH(CH(2))(n) were inversely proportional to linker length. Constraining the rigidity of the linker chain by incorporating

  双（9-甲基吩嗪-1-羧酰胺）通过各种不同的dicicic（CH（2））（n）（）NR（CH（2））（m）NR（CH（2））（n）接头连接通过使9-甲基吩嗪-1-羧酸咪唑啉化物与适当的多胺反应，制备了长度（羧酰胺NN距离为11.0至18.4A）和刚性。评价了这些化合物在P388白血病，Lewis肺癌以及野生型（JL（C））和突变型（JL（A）和JL（D））形式的人Jurkat白血病中具有低水平的拓扑异构酶II的生长抑制特性（拓扑II）。这些化合物在抗性Jurkat品系中均具有小于1的IC（50）比，这与对topo II的抑制作用不是主要的作用机理相一致。由（CH（2））（2）NR（CH（2））（2）NR（CH（2））（2）接头连接的类似物是非常有效的细胞毒素，对人类细胞系具有选择性，但是绝对效能从R = H到R = Me急剧下降到R = Pr和Bu。相反，（CH（2））（2）NR（CH（2
• Bis(phenazine-1-carboxamides):  Structure−Activity Relationships for a New Class of Dual Topoisomerase I/II-Directed Anticancer Drugs
  作者：Julie A. Spicer、Swarna A. Gamage、Gordon W. Rewcastle、Graeme J. Finlay、David J. A. Bridewell、Bruce C. Baguley、William A. Denny

  DOI：10.1021/jm990423f

  日期：2000.4.6

  Ring-substituted bis(phenazine-1-carboxamides), linked by a -(CH2)(3)NMe(CH2)(3)- chain, were prepared from the corresponding substituted phenazine-1-carboxylic acids by reaction of the intermediate imidazolides with bis(3-aminopropyl)methylamine. The compounds were evaluated for growth inhibitory activity in a panel of tumor cell lines, including P388 leukemia, Lewis lung carcinoma, and wild-type (JL(C)) and mutant (JL(A) and JL(D)) forms of human Jurkat leukemia; The latter mutant lines are resistant to topoisomerase (topo) II targeted agents because of lower levels of the enzyme. Analogues with small, lipophilic substituents (e.g,, Me, Cl) at the 9-position were the most potent inhibitors, superior to the corresponding dimeric bis(acridine-4-carboxamides) (bis-DACA analogues). Several of the compounds were preferentially (up to 2-fold) more cytotoxic toward the mutant Jurkat lines than the wild-type. To test whether this selectivity was related to topoisomerase action, the most potent of the compounds (9-methyl) was evaluated in a cell-free system. It poisoned topo I at drug concentrations of 0.25 and 0.5 mu M and inhibited the catalytic activity of both topo I and topo II at concentrations of 1 and 5 mu M, respectively. Results from the NCI human tumor cell line panel showed the compounds had preferential activity toward colon tumor lines ton average 9.5-fold more active in the HT29 line than in the cell line, panel as a whole). Several analogues produced significant growth delays in the relatively refractory subcutaneous colon 38 tumor model in vivo. In particular, the 9-methyl compound was substantially more potent in this tumor model than the clinical dual topo I/II poison DACA (total dose 90 versus 400 mg/kg) with comparable activity. The bis(phenazine-1-carboxamides) are a new and interesting class of dual topo I/II-directed anticancer drugs.