3,8-二氢-5,10-二羟基-2,7-双(羟基甲基)-3,8-二甲基嘧啶并[4,5-g]喹唑啉-4,9-二酮 | 143430-38-0

• 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: 3,8-二氢-5,10-二羟基-2,7-双(羟基甲基)-3,8-二甲基嘧啶并[4,5-g]喹唑啉-4,9-二酮
• 英文名称: 2,7-bis(hydroxymethyl)-5,10-dihydroxy-3,8-dimethylpyrimido<4,5-g>quinazoline-4,9(3H,8H)-dione
• 英文别名: 2,7-Bis(hydroxymethyl)-5,10-dihydroxy-3,8-dimethylpyrimido[4,5-g]quinazoline-4,9(3H,8H)-dione；5,10-Dihydroxy-2,7-bis(hydroxymethyl)-3,8-dimethylpyrimido[4,5-g]quinazoline-4,9-dione
• CAS: 143430-38-0
• 化学式: C₁₄H₁₄N₄O₆
• 分子量: 334.288
• InChiKey: WDXVUKHUYPCURK-UHFFFAOYSA-N

物化性质

• 沸点：
  695.0±65.0 °C(Predicted)
• 密度：
  1.80±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -1.1
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  146
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  3,8-二氢-5,10-二羟基-2,7-双(羟基甲基)-3,8-二甲基嘧啶并[4,5-g]喹唑啉-4,9-二酮 在 4-二甲氨基吡啶 、 ammonium cerium(IV) nitrate 、 甲基磺酰氯 、 lithium chloride 作用下， 以 水 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 6.33h， 生成 2,7-bis(chloromethyl)-3,8-dimethylpyrimido<4,5-g>quinazoline-4,5,9,10(3H,8H)-tetrone
  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：

  2,7-bis(methoxymethyl)-5,10-dimethoxy-3,8-dimethylpyrimido<4,5-g>quinazoline-4,9(3H,8H)-dione 在 三溴化硼 作用下， 以 苯 为溶剂， 反应 7.0h， 以72%的产率得到3,8-二氢-5,10-二羟基-2,7-双(羟基甲基)-3,8-二甲基嘧啶并[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.

  合成了吡咯并[4,5-g]喹唑啉醌衍生物作为类蒽醌样还原烷基化试剂。与许多天然存在的抗生素一样，这些醌衍生物被设计为在还原和离去基团消除后形成烷基化醌甲烯物种。对吡咯并[4,5-g]喹唑啉氢醌的动力学研究提供了醌甲烯中间体能够捕获亲核试剂（烷基化）和质子的证据。醌甲烯形成速率由氢醌的自由能确定。因此，通过绘制醌甲烯形成速率的对数与醌还原电位之间的关系图，获得了醌甲烯形成的线性自由能关系。吡咯并[4-5-g]喹唑啉醌甲烯落在这一自由能图上，表明这些物种是通过与此前在该研究小组中研究的其他结构多样的醌甲烯相同的机制形成的。许多醌类抗生素，特别是蒽环素，存在通过醌/氢醌循环形成有毒氧物种的缺点。在本发明中发现，吡咯并[4,5-g]喹唑啉氢醌对氧相对稳定，因此引起的氧毒性较小。抗肿瘤筛选显示，所披露的吡咯并[4,5-g]喹唑啉二酮衍生物对选定的人类癌细胞系具有出色的抑制活性。吡咯并[4,5-g]喹唑啉-二酮具有以下结构式：其中：R为H或CH3；X为Cl或Br。
• US5639881A
  申请人：——

  公开号：US5639881A

  公开（公告）日：1997-06-17
• 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
  作者：Robert H. Lemus、Edward B. Skibo

  DOI：10.1021/jo00047a017

  日期：1992.10

  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.