3-benzyl-2,5-dimethoxy-2,5-cyclohexadiene-1,4-dione | 586963-67-9

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3-benzyl-2,5-dimethoxy-2,5-cyclohexadiene-1,4-dione
• 英文别名: 3-Benzyl-2,5-dimethoxycyclohexa-2,5-diene-1,4-dione
• CAS: 586963-67-9
• 化学式: C₁₅H₁₄O₄
• 分子量: 258.274
• InChiKey: BUOKSRVVRDZSJS-UHFFFAOYSA-N

物化性质

• 沸点：
  431.9±45.0 °C(Predicted)
• 密度：
  1.21±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  52.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-benzyl-2,5-dimethoxy-2,5-cyclohexadiene-1,4-dione 在 氢氧化钾 作用下， 以 甲醇 为溶剂， 反应 12.0h， 以68%的产率得到3-benzyl-2-hydroxy-5-methoxy-2,5-cyclohexadiene-1,4-dione
  参考文献：
  名称：

  Development of Natural Product-Derived Receptor Tyrosine Kinase Inhibitors Based on Conservation of Protein Domain Fold

  摘要：

  Receptor tyrosine kinases (RTKs) such as Tie-2, IGF1R, Her-2/Neu, EGFR, and VEGFR1-3 play crucial roles in the control of cell growth and differentiation. Inhibition of such RTKs has become a major focus of current anticancer drug development, and therefore the discovery of new classes of inhibitors for these signal-transducing proteins is of prime importance. We have recently proposed a novel concept for improving the hit-finding process by employing natural products as biologically validated starting points in structural space for compound library development. In this concept, natural products are regarded as evolutionary chosen ligands for protein domains which are structurally conserved yet genetically mobile. Here we report on the discovery of novel and highly selective VEGFR-2 and -3, Tie-2, and IGF1R inhibitors derived from the naturally occurring Her-2/Neu kinase inhibitor nakijiquinone C and developed on the basis of this concept. Based on the structure of the natural product, a small library (74 members) was synthesized and investigated for inhibition of kinases with highly similar ATP-binding domains. The library yielded inhibitors with IC(50)s in the low micromolar range with high frequency (7 out of 74). In particular, four inhibitors of Tie-2 were found, a kinase critically involved in the formation of new blood vessels from preexisting ones (angiogenesis) and believed to be a new promising target in antitumor therapy. These results support the "domain concept". To advance the development of improved inhibitors, extensive molecular modeling studies were undertaken, including the construction of new homology models for VEGFR-2 and Tie-2. These studies revealed residues in the kinase structure which are crucial to the development of tailor-made receptor tyrosine kinase inhibitors.

  DOI：

  10.1021/jm0307943
• 作为产物：
  描述：

  2-异丙氧基苯酚 在 sodium hydroxide 、 sodium tetrahydroborate 、 sodium hydrogen sulfate 、 copper(l) iodide 、 正丁基锂 、 salcomine 、 potassium nitrososulfonate 、 溴 、 氧气 、 三氯化硼 、 甲基三辛基氯化铵 、 sodium carbonate 、 叔丁胺 作用下， 以 四氢呋喃 、 乙醇 、 正己烷 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 、 苯 为溶剂， 反应 28.5h， 生成 3-benzyl-2,5-dimethoxy-2,5-cyclohexadiene-1,4-dione
  参考文献：
  名称：

  Development of Natural Product-Derived Receptor Tyrosine Kinase Inhibitors Based on Conservation of Protein Domain Fold

  摘要：

  Receptor tyrosine kinases (RTKs) such as Tie-2, IGF1R, Her-2/Neu, EGFR, and VEGFR1-3 play crucial roles in the control of cell growth and differentiation. Inhibition of such RTKs has become a major focus of current anticancer drug development, and therefore the discovery of new classes of inhibitors for these signal-transducing proteins is of prime importance. We have recently proposed a novel concept for improving the hit-finding process by employing natural products as biologically validated starting points in structural space for compound library development. In this concept, natural products are regarded as evolutionary chosen ligands for protein domains which are structurally conserved yet genetically mobile. Here we report on the discovery of novel and highly selective VEGFR-2 and -3, Tie-2, and IGF1R inhibitors derived from the naturally occurring Her-2/Neu kinase inhibitor nakijiquinone C and developed on the basis of this concept. Based on the structure of the natural product, a small library (74 members) was synthesized and investigated for inhibition of kinases with highly similar ATP-binding domains. The library yielded inhibitors with IC(50)s in the low micromolar range with high frequency (7 out of 74). In particular, four inhibitors of Tie-2 were found, a kinase critically involved in the formation of new blood vessels from preexisting ones (angiogenesis) and believed to be a new promising target in antitumor therapy. These results support the "domain concept". To advance the development of improved inhibitors, extensive molecular modeling studies were undertaken, including the construction of new homology models for VEGFR-2 and Tie-2. These studies revealed residues in the kinase structure which are crucial to the development of tailor-made receptor tyrosine kinase inhibitors.

  DOI：

  10.1021/jm0307943

文献信息

• Development of Natural Product-Derived Receptor Tyrosine Kinase Inhibitors Based on Conservation of Protein Domain Fold
  作者：Lars Kissau、Petra Stahl、Ralph Mazitschek、Athannasios Giannis、Herbert Waldmann

  DOI：10.1021/jm0307943

  日期：2003.7.1

  Receptor tyrosine kinases (RTKs) such as Tie-2, IGF1R, Her-2/Neu, EGFR, and VEGFR1-3 play crucial roles in the control of cell growth and differentiation. Inhibition of such RTKs has become a major focus of current anticancer drug development, and therefore the discovery of new classes of inhibitors for these signal-transducing proteins is of prime importance. We have recently proposed a novel concept for improving the hit-finding process by employing natural products as biologically validated starting points in structural space for compound library development. In this concept, natural products are regarded as evolutionary chosen ligands for protein domains which are structurally conserved yet genetically mobile. Here we report on the discovery of novel and highly selective VEGFR-2 and -3, Tie-2, and IGF1R inhibitors derived from the naturally occurring Her-2/Neu kinase inhibitor nakijiquinone C and developed on the basis of this concept. Based on the structure of the natural product, a small library (74 members) was synthesized and investigated for inhibition of kinases with highly similar ATP-binding domains. The library yielded inhibitors with IC(50)s in the low micromolar range with high frequency (7 out of 74). In particular, four inhibitors of Tie-2 were found, a kinase critically involved in the formation of new blood vessels from preexisting ones (angiogenesis) and believed to be a new promising target in antitumor therapy. These results support the "domain concept". To advance the development of improved inhibitors, extensive molecular modeling studies were undertaken, including the construction of new homology models for VEGFR-2 and Tie-2. These studies revealed residues in the kinase structure which are crucial to the development of tailor-made receptor tyrosine kinase inhibitors.