[4-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-piperazin-1-yl]-(4-trifluoromethyl-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-trifluoromethyl-phenyl)-methanone
• 英文别名: [4-(4-Amino-6,7-dimethoxyquinazolin-2-yl)piperazin-1-yl]-[4-(trifluoromethyl)phenyl]methanone
• 化学式: C₂₂H₂₂F₃N₅O₃
• 分子量: 461.444
• InChiKey: QLBUKZISRKRNBR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  33
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  93.8
• 氢给体数：
  1
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  4-三氟甲基苯甲酸 在 氯化亚砜 、 三乙胺 作用下， 以 1,4-二氧六环 、 甲苯 为溶剂， 反应 25.0h， 生成 [4-(4-amino-6,7-dimethoxy-quinazolin-2-yl)-piperazin-1-yl]-(4-trifluoromethyl-phenyl)-methanone
  参考文献：
  名称：

  Analogues of Prazosin That Bear a Benextramine-Related Polyamine Backbone Exhibit Different Antagonism toward α₁-Adrenoreceptor Subtypes

  摘要：

  Hybrid tetraaamine disulfides 4-9 were synthesized by combining the structural features of prazosin (1), a competitive alpha (1)-adrenoreceptor antagonist, and benextramine (2), an irreversible alpha (1)/alpha (2)-adrenoreceptor antagonist, and their biological profiles at alpha (1)-adrenoreceptor subtypes were assessed by functional experiments in isolated rat vas deferens (alpha (1A)), spleen (alpha (1B)), and aorta (alpha (1D)). To verify the role of the disulfide moiety on the interaction with alpha (1)-adrenorcceptor subtypes, carbon analogues 10-15 were included in this study. All quinazolines lacking the disulfide bridge behaved, like 1, as competitive antagonists, whereas all polyamine disulfides displayed a nonhomogeneous mechanism of inhibition at the three subtypes since they were, like 2, noncompetitive antagonists at the alpha (1A) and alpha (1B) subtypes while being, unlike 2, competitive antagonists at the alpha (1D). In particular, the blocking effects were characterized by a decrease of the maximal response to noradrenaline that was affected only slightly by washings. Probably the alpha (1A) and alpha (1B) subtypes bear in the binding pocket a suitable thiol function that would suffer an interchange reaction with the disulfide moiety of the antagonist and which is missing, or not accessible, in the alpha (1D) subtype. Polyamines 8, 9, and 14, among others, emerged as promising tools for the characterization of al-adrenoreceptors, owing to their receptor subtype selectivity. Finally, the effect of nonbasic substituents on the phenyl ring of prazosin analogues 16-28 on potency and selectivity for the different subtypes can hardly be rationalized.

  DOI：

  10.1021/jm000995w

文献信息

• 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.
• Analogues of Prazosin That Bear a Benextramine-Related Polyamine Backbone Exhibit Different Antagonism toward α₁-Adrenoreceptor Subtypes
  作者：Maria L. Bolognesi、Gabriella Marucci、Piero Angeli、Michela Buccioni、Anna Minarini、Michela Rosini、Vincenzo Tumiatti、Carlo Melchiorre

  DOI：10.1021/jm000995w

  日期：2001.2.1

  Hybrid tetraaamine disulfides 4-9 were synthesized by combining the structural features of prazosin (1), a competitive alpha (1)-adrenoreceptor antagonist, and benextramine (2), an irreversible alpha (1)/alpha (2)-adrenoreceptor antagonist, and their biological profiles at alpha (1)-adrenoreceptor subtypes were assessed by functional experiments in isolated rat vas deferens (alpha (1A)), spleen (alpha (1B)), and aorta (alpha (1D)). To verify the role of the disulfide moiety on the interaction with alpha (1)-adrenorcceptor subtypes, carbon analogues 10-15 were included in this study. All quinazolines lacking the disulfide bridge behaved, like 1, as competitive antagonists, whereas all polyamine disulfides displayed a nonhomogeneous mechanism of inhibition at the three subtypes since they were, like 2, noncompetitive antagonists at the alpha (1A) and alpha (1B) subtypes while being, unlike 2, competitive antagonists at the alpha (1D). In particular, the blocking effects were characterized by a decrease of the maximal response to noradrenaline that was affected only slightly by washings. Probably the alpha (1A) and alpha (1B) subtypes bear in the binding pocket a suitable thiol function that would suffer an interchange reaction with the disulfide moiety of the antagonist and which is missing, or not accessible, in the alpha (1D) subtype. Polyamines 8, 9, and 14, among others, emerged as promising tools for the characterization of al-adrenoreceptors, owing to their receptor subtype selectivity. Finally, the effect of nonbasic substituents on the phenyl ring of prazosin analogues 16-28 on potency and selectivity for the different subtypes can hardly be rationalized.