[4-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-piperazin-1-yl]-(4-chloro-phenyl)-methanone

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪烷类
• 英文名称: [4-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-piperazin-1-yl]-(4-chloro-phenyl)-methanone
• 英文别名: [4-(4-Amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-(4-chlorophenyl)methanone
• 化学式: C₂₁H₂₂ClN₅O₃
• 分子量: 427.89
• InChiKey: BFNSEIRNBRGZCZ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  93.8
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  2-氯-4-氨基-6,7-二甲氧基喹唑啉 在 palladium on activated charcoal 氢气 、 三乙胺 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 、 正丁醇 为溶剂， 反应 10.0h， 生成 [4-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-piperazin-1-yl]-(4-chloro-phenyl)-methanone
  参考文献：
  名称：

  Pharmacological Exploitation of the α1-Adrenoreceptor Antagonist Doxazosin to Develop a Novel Class of Antitumor Agents That Block Intracellular Protein Kinase B/Akt Activation

  摘要：

  The alpha1-adrenoreceptor antagonist doxazosin induces apoptosis in malignant cells with moderate potency via an alpha1-adrenoreceptor-independent mechanism. Here, we demonstrate that the ability of doxazosin to induce apoptosis in PC-3 prostate cancer cells was, in part, attributable to the inhibition of protein kinase B (PKB)/Akt activation. The separation of the effect of doxazosin on apoptosis from its original pharmacological activity provides molecular underpinnings to develop novel antitumor agents. Replacement of the (2,3-dihydro-benzo[1,4]dioxane)-carbonyl moiety of doxazosin with aryl-sulfonyl functions dramatically improves the potency in facilitating Akt deactivation and inducing apoptosis. The optimal compounds, 33 and 44, were effective in apoptosis induction at low micromolar concentrations irrespective of androgen dependency and p53 functional status. Both agents were active in suppressing the growth of a panel of 60 cancer-cell lines with IC50 values of 2.2 and 1.5 muM, respectively. Together, these in vitro efficacy data suggest the translational potential of these agents in prostate cancer treatment.

  DOI：

  10.1021/jm049752k

文献信息

• NOVEL ANTITUMOR AGENTS AND METHODS OF THEIR USE
  申请人：Chen Ching-Shih

  公开号：US20090048265A1

  公开（公告）日：2009-02-19

  Antitumor compounds based on the α1-adrenoceptor antagonist, doxazosin, as well as compositions and methods of use. The disclosed compounds induce apoptosis in cancer cells.

  基于α1-肾上腺素能受体拮抗剂多沙唑嗪的抗肿瘤化合物，以及其组合物和使用方法。所披露的化合物能诱导癌细胞凋亡。
• [EN] AMINO-QUINAZOLINE DERIVATIVES AS ANTITUMOR AGENTS<br/>[FR] NOUVEAUX AGENTS ANTITUMORAUX ET METHODES D'UTILISATION DE CES DERNIERS
  申请人：UNIV OHIO STATE RES FOUND

  公开号：WO2006002088A3

  公开（公告）日：2006-07-13
• US8377948B2
  申请人：——

  公开号：US8377948B2

  公开（公告）日：2013-02-19
• [EN] NOVEL ANTITUMOUR AGENTS AND METHODS OF THEIR USE<br/>[FR] NOUVEAUX AGENTS ANTITUMORAUX ET METHODES D'UTILISATION DE CES DERNIERS
  申请人：UNIV OHIO STATE RES FOUND

  公开号：WO2006002088A2

  公开（公告）日：2006-01-05

  Antitumor compounds based on the α1-adrenoceptor antagonist, doxazosin, as well as compositions and methods of use. The disclosed compounds induce apoptosis in cancer cells.
• Pharmacological Exploitation of the α1-Adrenoreceptor Antagonist Doxazosin to Develop a Novel Class of Antitumor Agents That Block Intracellular Protein Kinase B/Akt Activation
  作者：Yeng-Jeng Shaw、Ya-Ting Yang、Jason B. Garrison、Natasha Kyprianou、Ching-Shih Chen

  DOI：10.1021/jm049752k

  日期：2004.8.1

  The alpha1-adrenoreceptor antagonist doxazosin induces apoptosis in malignant cells with moderate potency via an alpha1-adrenoreceptor-independent mechanism. Here, we demonstrate that the ability of doxazosin to induce apoptosis in PC-3 prostate cancer cells was, in part, attributable to the inhibition of protein kinase B (PKB)/Akt activation. The separation of the effect of doxazosin on apoptosis from its original pharmacological activity provides molecular underpinnings to develop novel antitumor agents. Replacement of the (2,3-dihydro-benzo[1,4]dioxane)-carbonyl moiety of doxazosin with aryl-sulfonyl functions dramatically improves the potency in facilitating Akt deactivation and inducing apoptosis. The optimal compounds, 33 and 44, were effective in apoptosis induction at low micromolar concentrations irrespective of androgen dependency and p53 functional status. Both agents were active in suppressing the growth of a panel of 60 cancer-cell lines with IC50 values of 2.2 and 1.5 muM, respectively. Together, these in vitro efficacy data suggest the translational potential of these agents in prostate cancer treatment.