3-(4-hydroxy-3,5-dimethoxyphenyl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione | 1215294-02-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 酚类
• 英文名称: 3-(4-hydroxy-3,5-dimethoxyphenyl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione
• 英文别名: 3-(4-hydroxy-3,5-dimethoxyphenyl)-4-(1H-indol-3-yl)pyrrole-2,5-dione
• CAS: 1215294-02-2
• 化学式: C₂₀H₁₆N₂O₅
• 分子量: 364.357
• InChiKey: IKVQTFSPGOTIPQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.1
• 拓扑面积：
  101
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  [11C]methyl iodide 、 3-(4-hydroxy-3,5-dimethoxyphenyl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione 在 sodium hydroxide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 3-(1H-indol-3-yl)-4-(3,5-dimethoxy-4-([(11)C]-methoxy)phenyl)-1H-pyrrole-2,5-dione
  参考文献：
  名称：

  Labeled 3-aryl-4-indolylmaleimide derivatives and their potential as angiogenic PET biomarkers

  摘要：

  In a continued effort to find a suitable PET tracer for visualization of angiogenic processes, we explored the 3,4-diarylmaleimide family, known to have high affinity and selectivity towards the VEGFR-TKs. One previously reported agent and three new halogen-containing 3,4-diarylmaleimide derivatives were synthesized. The four maleimide derivatives were evaluated for their affinity and selectivity towards the VEGFRs and exhibited promising results. An automated carbon-11 radiolabeling route with a total synthesis time of 50 min successfully labeled the lead compound, resulting in 1.55 +/- 0.15 GBq of tracer with a radiochemical yield of 20 +/- 2%, 96% radiochemical purity and a SA of 111 +/- 22 GBq/mu mol (EOB, n = 5). The tracer possessed high stability in in vitro blood stability tests and specific VEGFR-TK binding profiles in intact cell binding experiments. Tracer lipophilicity was evaluated in an n-octanol/phosphate buffer system giving a Log D-7.4 of 1.99 +/- 0.04. For the in vivo experiments, two animal models were used. The first was a U87 glioma tumor model, frequently reported in the literature and the second, a newly developed 293/KDR tumor model. Both models were validated for VEGFR-2 expression and used in in vivo biodistribution studies. These studies revealed low accumulation and rapid washout of the tracer from tumor tissue. High accumulation of activity in the liver prompted us to examine the tracer's in vitro stability to liver microsomes, revealing low resistance to P450 metabolism. In spite of encouraging in vitro results, the labeled lead tracer failed to accumulate in VEGFR-2 overexpressing tumors. It is possible that poor resistance to P450 metabolism reduces tracer's circulation leading to low tumor accumulation. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.12.004
• 作为产物：
  描述：

  3-(4-benzyloxy-3,5-dimethoxyphenyl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione 在 palladium 10% on activated carbon 、 氢气 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 2.0h， 以67%的产率得到3-(4-hydroxy-3,5-dimethoxyphenyl)-4-(1H-indol-3-yl)-1H-pyrrole-2,5-dione
  参考文献：
  名称：

  Labeled 3-aryl-4-indolylmaleimide derivatives and their potential as angiogenic PET biomarkers

  摘要：

  In a continued effort to find a suitable PET tracer for visualization of angiogenic processes, we explored the 3,4-diarylmaleimide family, known to have high affinity and selectivity towards the VEGFR-TKs. One previously reported agent and three new halogen-containing 3,4-diarylmaleimide derivatives were synthesized. The four maleimide derivatives were evaluated for their affinity and selectivity towards the VEGFRs and exhibited promising results. An automated carbon-11 radiolabeling route with a total synthesis time of 50 min successfully labeled the lead compound, resulting in 1.55 +/- 0.15 GBq of tracer with a radiochemical yield of 20 +/- 2%, 96% radiochemical purity and a SA of 111 +/- 22 GBq/mu mol (EOB, n = 5). The tracer possessed high stability in in vitro blood stability tests and specific VEGFR-TK binding profiles in intact cell binding experiments. Tracer lipophilicity was evaluated in an n-octanol/phosphate buffer system giving a Log D-7.4 of 1.99 +/- 0.04. For the in vivo experiments, two animal models were used. The first was a U87 glioma tumor model, frequently reported in the literature and the second, a newly developed 293/KDR tumor model. Both models were validated for VEGFR-2 expression and used in in vivo biodistribution studies. These studies revealed low accumulation and rapid washout of the tracer from tumor tissue. High accumulation of activity in the liver prompted us to examine the tracer's in vitro stability to liver microsomes, revealing low resistance to P450 metabolism. In spite of encouraging in vitro results, the labeled lead tracer failed to accumulate in VEGFR-2 overexpressing tumors. It is possible that poor resistance to P450 metabolism reduces tracer's circulation leading to low tumor accumulation. (C) 2009 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2009.12.004

文献信息

• 3-(5-fluoroindolyl)-4-arylmaleimide compounds and their use in tumor treatment
  申请人：JOHANNES GUTENBERG-UNIVERSITÄT MAINZ

  公开号：US11045449B2

  公开（公告）日：2021-06-29

  The present invention relates to 3-(5-fluoroindolyl)-4-arylmaleimide compounds and pharmaceutical compositions containing them. The compounds of the present invention are protein kinases (GSK-3beta, VEGFR-2 and FLT-3) with antineoplastic activity. They can therefore be used for the treatment or prevention of tumors, in particular solid tumors.

  本发明涉及 3-(5-氟吲哚基)-4-芳基马来酰亚胺化合物及其药物组合物。本发明的化合物是具有抗肿瘤活性的蛋白激酶（GSK-3beta、VEGFR-2 和 FLT-3）。因此，它们可用于治疗或预防肿瘤，特别是实体瘤。
• 3-(5-FLUOROINDOLYL)-4-ARYLMALEIMIDE COMPOUNDS AND THEIR USE IN TUMOR TREATMENT
  申请人：Johannes-Gutenberg-Universität Mainz

  公开号：EP3397632B1

  公开（公告）日：2020-06-24
• 3-(5-Fluoroindolyl)-4-arylmaleimide Compounds and their Use in Tumor Treatment
  申请人：JOHANNES GUTENBERG-UNIVERSITÄT MAINZ

  公开号：US20200253930A1

  公开（公告）日：2020-08-13

  The present invention relates to 3-(5-fluoroindolyl)-4-arylmaleimide compounds and pharmaceutical compositions containing them. The compounds of the present invention are protein kinases (GSK-3beta, VEGFR-2 and FLT-3) with antineoplastic activity. They can therefore be used for the treatment or prevention of tumors, in particular solid tumors.
• [EN] 3-(5-FLUOROINDOLYL)-4-ARYLMALEIMIDE COMPOUNDS AND THEIR USE IN TUMOR TREATMENT<br/>[FR] COMPOSÉS 3-(5-FLUOROINDOLYL)-4-ARYLMALÉIMIDE ET LEUR UTILISATION DANS LE TRAITEMENT DES TUMEURS
  申请人：JOHANNES GUTENBERG-UNIVERSITÄT MAINZ

  公开号：WO2017114863A1

  公开（公告）日：2017-07-06

  The present invention relates to 3-(5-fluoroindolyl)-4-arylmaleimide compounds and pharmaceutical compositions containing them. The compounds of the present invention are protein kinases (GSK-3beta, VEGFR-2 and FLT-3) with antineoplastic activity. They can therefore be used for the treatment or prevention of tumors, in particular solid tumors.