(9CI)-1,6-二氢-5,10-二甲氧基-2,7-双(苯氧基甲基)-嘧啶并[4,5-g]喹唑啉-4,9-二酮 | 143430-32-4

• 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: (9CI)-1,6-二氢-5,10-二甲氧基-2,7-双(苯氧基甲基)-嘧啶并[4,5-g]喹唑啉-4,9-二酮
• 英文名称: 2,7-bis(phenoxymethyl)-5,10-dimethoxypyrimido<4,5-g>quinazoline-4,9(3H,8H)-dione
• 英文别名: 2,7-Bis (phenoxymethyl)-5,10-dimethoxyprimido[4,5-g]quinazoline-4,9(3H,8H)-dione；5,10-dimethoxy-2,7-bis(phenoxymethyl)-3,8-dihydropyrimido[4,5-g]quinazoline-4,9-dione
• CAS: 143430-32-4
• 化学式: C₂₆H₂₂N₄O₆
• 分子量: 486.484
• InChiKey: KBFDNMNGOPZBGV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  36
• 可旋转键数：
  8
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  120
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (9CI)-1,6-二氢-5,10-二甲氧基-2,7-双(苯氧基甲基)-嘧啶并[4,5-g]喹唑啉-4,9-二酮 在 三溴化硼 作用下， 以 二氯甲烷 、 苯 为溶剂， 反应 5.0h， 以71%的产率得到(9CI)-2,7-双(溴甲基)-1,6-二氢-5,10-二羟基嘧啶并[4,5-g]喹唑啉-4,9-二酮
  参考文献：
  名称：

  Design of pyrimido[4,5-g]quinazoline-based anthraquinone mimics. Structure-activity relationship for quinone methide formation and the influence of internal hydrogen bonds on quinone methide fate

  摘要：

  Pyrimido[4,5-g]quinazolinequinone derivatives were synthesized as a anthraquinone-like reductive alkylating agents. Like many naturally-occurring antibiotics, these quinone derivatives are designed to afford an alkylating quinone methide species upon reduction and leaving-group elimination. Kinetic studies of pyrimido[4,5-g]quinazoline hydroquinones provided evidence of quinone methide intermediate able to trap nucleophiles (alkylation) and protons (ketonization). The rate of quinone methide formation is determined by the hydroquinone free energy. Thus, a linear free energy relationship for quinone methide formation was obtained by plotting rates of quinone methide formation as the log versus the quinone reduction potential. The pyrimido[4,5-g]quinazoline quinone methides fall on this free energy plot, showing that these species are formed by the same mechanism as the other structurally-diverse quinone methides previously studied in this research group. Internal hydrogen bonds present in pyrimido[4,5-g]quinazoline derivatives influence the fate of the quinone methide species as well as the rate of hydroquinone oxidation in the presence of oxygen Such hydrogen bonds stabilize the hydroquinone species, thereby resulting in slow rates of hydroquinone oxidation to quinone in alkaline aerobic buffer. Stabilization of the hydroquinone also results in substantial nucleophile trapping by the quinone methide. Without internal hydrogen bonds, hydroquinone oxidations are rapid and the quinone methide traps only electrophiles.

  DOI：

  10.1021/jo00047a017
• 作为产物：
  描述：

  2,5-Dimethoxy-1,4-benzoldicarbonitril 在 palladium on activated charcoal sodium hydroxide 、 nitronium tetrafluoborate 、 硫酸 、 氨 、 氢气 、 双氧水 、 硝酸 、 乙酸酐 、 三乙胺 、 sodium nitrite 作用下， 以 甲醇 、 乙醇 、 溶剂黄146 、 乙腈 、 苯 为溶剂， 25.0~70.0 ℃ 、344.73 kPa 条件下， 反应 24.58h， 生成 (9CI)-1,6-二氢-5,10-二甲氧基-2,7-双(苯氧基甲基)-嘧啶并[4,5-g]喹唑啉-4,9-二酮
  参考文献：
  名称：

  Design of pyrimido[4,5-g]quinazoline-based anthraquinone mimics. Structure-activity relationship for quinone methide formation and the influence of internal hydrogen bonds on quinone methide fate

  摘要：

  Pyrimido[4,5-g]quinazolinequinone derivatives were synthesized as a anthraquinone-like reductive alkylating agents. Like many naturally-occurring antibiotics, these quinone derivatives are designed to afford an alkylating quinone methide species upon reduction and leaving-group elimination. Kinetic studies of pyrimido[4,5-g]quinazoline hydroquinones provided evidence of quinone methide intermediate able to trap nucleophiles (alkylation) and protons (ketonization). The rate of quinone methide formation is determined by the hydroquinone free energy. Thus, a linear free energy relationship for quinone methide formation was obtained by plotting rates of quinone methide formation as the log versus the quinone reduction potential. The pyrimido[4,5-g]quinazoline quinone methides fall on this free energy plot, showing that these species are formed by the same mechanism as the other structurally-diverse quinone methides previously studied in this research group. Internal hydrogen bonds present in pyrimido[4,5-g]quinazoline derivatives influence the fate of the quinone methide species as well as the rate of hydroquinone oxidation in the presence of oxygen Such hydrogen bonds stabilize the hydroquinone species, thereby resulting in slow rates of hydroquinone oxidation to quinone in alkaline aerobic buffer. Stabilization of the hydroquinone also results in substantial nucleophile trapping by the quinone methide. Without internal hydrogen bonds, hydroquinone oxidations are rapid and the quinone methide traps only electrophiles.

  DOI：

  10.1021/jo00047a017

文献信息

• Synthesis and elucidation of pyrimido (4,5-Q) quinazoline derivatives
  申请人：Arizona Board of Regents acting on behalf of Arizona State University

  公开号：US05639881A1

  公开（公告）日：1997-06-17

  Pyrimido[4,5-g]quinazoline quinone derivatives were synthesized as anthranone-like reductive alkylating agents. Like many naturally-occurring antibiotics, these quinone derivatives are designed to afford an alkylating quinone methide species upon reduction and leaving group elimination. Kinetic studies of pyrimido[4,5-g]quinazoline hydroquinones provided evidence of quinone methide intermediates able to trap nucleophiles (alkylation) and protons. The rate of quinone methide formation is determined by the hydroquinone free energy. Thus, a linear free energy relationship for quinone methide formation was obtained by plotting rates of quinone methide formation, as the log, versus the quinone reduction potential. The pyrimido[4-5-g]quinazoline quinone methides fall on this free energy plot, showing that these species are formed by the same mechanism as the other structurally-diverse quinone methides previously studied in this research group. A drawback of many quinone antibiotics, particularly the anthracyclines, is the formation of toxic oxygen species by quinone/hydroquinone cycling. In the present invention pyrimido[4,5-g]quinazoline hydroquinones are found to be relatively stable toward oxygen, and thus cause little oxygen toxicity. Antitumor screening revealed that the disclosed pyrimido[4,5-g]quinazoline dione derivatives possess excellent inhibitory activity against selected human cancer cell lines. The pyrimido[4,5g]quinazoline-diones have the following structural formulae: ##STR1## wherein: R is H or CH.sub.3 ; and X is Cl or Br.

  合成了嘧啶并[4,5-g]喹唑啉醌衍生物作为类蒽醌还原烷基化试剂。与许多天然抗生素一样，这些醌衍生物旨在在还原和离去基消除后提供烷基化醌甲烷物种。嘧啶并[4,5-g]喹唑啉羟醌的动力学研究提供了醌甲烷中间体的证据，能够捕获亲核试剂（烷基化）和质子。醌甲烷形成的速率由羟醌自由能决定。因此，通过绘制醌还原电位的对数，以及醌甲烷形成速率，得到了醌甲烷形成的线性自由能关系。嘧啶并[4-5-g]喹唑啉醌甲烷落在这个自由能图上，表明这些物种是通过与先前在该研究小组中研究的其他结构多样的醌甲烷相同的机制形成的。许多醌类抗生素，特别是蒽环素的缺点是通过醌/羟醌循环形成有毒氧化物质。在本发明中，发现嘧啶并[4,5-g]喹唑啉羟醌相对稳定于氧气，因此产生的氧毒性很小。抗肿瘤筛选显示，所述的嘧啶并[4,5-g]喹唑啉二酮衍生物对选择的人类癌细胞系具有优异的抑制活性。嘧啶并[4,5-g]喹唑啉二酮的结构式为：其中：R为H或CH3；X为Cl或Br。