2-Hydroxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide

• 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-Hydroxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide
• 化学式: C₂₁H₂₀N₄O₂
• 分子量: 360.415
• InChiKey: COESGAYETSYBTN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.93
• 重原子数：
  27.0
• 可旋转键数：
  4.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.19
• 拓扑面积：
  78.35
• 氢给体数：
  2.0
• 氢受体数：
  5.0

反应信息

• 作为产物：
  描述：

  1-氨基-7-萘酚 在 N-乙基吗啉 、 sodium tetrahydroborate 、 sodium thioethoxide 、 sodium ethanolate 、 铜 、 sodium hydride 、 copper(l) chloride 作用下， 以 乙醇 、 乙二醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 80.5h， 生成 2-Hydroxy-benzo[a]phenazine-11-carboxylic acid (2-dimethylamino-ethyl)-amide
  参考文献：
  名称：

  Novel Angular Benzophenazines:  Dual Topoisomerase I and Topoisomerase II Inhibitors as Potential Anticancer Agents

  摘要：

  A series of substituted angular benzophenazines were prepared using a new synthetic route via a novel regiocontrolled condensation of 1,2-naphthoquinones and 2,3-diaminobenzoic acids. The synthesis and biological activity of this new series of substituted 8,9-benzo[a]phenazine carboxamide systems are described. The analogues were evaluated against the H69 parental human small cell lung carcinoma cell line and H69/LX4 resistant cell line which overexpresses P-glycoprotein. Selected analogues were evaluated against the COR-L23-parental human non small cell lung carcinoma cell line and the COR-L23/R resistant cell line which overexpresses multidrug resistance protein. This series of novel angular benzophenazines were potent cytotoxic agents in these cell lines and may be able to circumvent multidrug resistance mechanisms which result in the lack of efficacy of many drugs in cancer chemotherapy. These compounds show dual inhibition of topoisomerase I and topoisomerase II and thus target two key enzymes responsible for the topology of DNA that are active at different points in the cell cycle. The introduction of chirality into the carboxamide side chain of these novel benzophenazine carboxamides has resulted in the discovery of a potent enantiospecific series of cytotoxic agents, exemplified by 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)methyl-ethyl)-amide, XR11576 ((R)-4j"). In vivo activity has been demonstrated for 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576, after intravenous administration to female mice, and this compound has been selected as a development candidate for further evaluation.

  DOI：

  10.1021/jm010329a

文献信息

• Novel Angular Benzophenazines:  Dual Topoisomerase I and Topoisomerase II Inhibitors as Potential Anticancer Agents
  作者：Nigel Vicker、Luke Burgess、Irina S. Chuckowree、Rory Dodd、Adrian J. Folkes、David J. Hardick、Timothy C. Hancox、Warren Miller、John Milton、Sukhjit Sohal、Shouming Wang、Stephen P. Wren、Peter A. Charlton、Wendy Dangerfield、Chris Liddle、Prakash Mistry、Alistair J. Stewart、William A. Denny

  DOI：10.1021/jm010329a

  日期：2002.1.1

  A series of substituted angular benzophenazines were prepared using a new synthetic route via a novel regiocontrolled condensation of 1,2-naphthoquinones and 2,3-diaminobenzoic acids. The synthesis and biological activity of this new series of substituted 8,9-benzo[a]phenazine carboxamide systems are described. The analogues were evaluated against the H69 parental human small cell lung carcinoma cell line and H69/LX4 resistant cell line which overexpresses P-glycoprotein. Selected analogues were evaluated against the COR-L23-parental human non small cell lung carcinoma cell line and the COR-L23/R resistant cell line which overexpresses multidrug resistance protein. This series of novel angular benzophenazines were potent cytotoxic agents in these cell lines and may be able to circumvent multidrug resistance mechanisms which result in the lack of efficacy of many drugs in cancer chemotherapy. These compounds show dual inhibition of topoisomerase I and topoisomerase II and thus target two key enzymes responsible for the topology of DNA that are active at different points in the cell cycle. The introduction of chirality into the carboxamide side chain of these novel benzophenazine carboxamides has resulted in the discovery of a potent enantiospecific series of cytotoxic agents, exemplified by 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)methyl-ethyl)-amide, XR11576 ((R)-4j"). In vivo activity has been demonstrated for 4-methoxy-benzo[a]phenazine-11-carboxylic acid (2-(dimethylamino)-1-(R)-methyl-ethyl)-amide, XR11576, after intravenous administration to female mice, and this compound has been selected as a development candidate for further evaluation.