PD 47824 | 622864-54-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 中文名称: PD 47824
• 英文名称: PD 407824
• 英文别名: 9-hydroxy-4-phenyl-pyrrolo [3,4-c]carbazole-1,3(2H,6H)-dione；9-Hydroxy-4-phenylpyrrolo[3,4-C]carbazole-1,3(2H,6H)-dione；9-hydroxy-4-phenyl-6H-pyrrolo[3,4-c]carbazole-1,3-dione
• CAS: 622864-54-4
• 化学式: C₂₀H₁₂N₂O₃
• 分子量: 328.327
• InChiKey: IAUZTOZLTFSMIE-UHFFFAOYSA-N

物化性质

• 密度：
  1.507±0.06 g/cm3(Predicted)
• 溶解度：
  二甲基亚砜：>10mg/mL

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  25
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  82.2
• 氢给体数：
  3
• 氢受体数：
  3

安全信息

• WGK Germany：
  3

反应信息

• 作为反应物：
  描述：

  PD 47824 在 一水合肼 、 硫酸 作用下， 以 乙醇 为溶剂， 反应 0.5h， 以80%的产率得到2-amino-9-hydroxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione
  参考文献：
  名称：

  4-Phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione Inhibitors of the Checkpoint Kinase Wee1. Structure−Activity Relationships for Chromophore Modification and Phenyl Ring Substitution

  摘要：

  High-throughput screening has identified a novel class of inhibitors of the checkpoint kinase Wee1, which have potential for use in cancer chemotherapy. These inhibitors are based on a 4-phenylpyrrolo[3,4-c]carbazole- 1,3(2H,6H)-dione template and have been shown by X-ray crystallography to bind at the ATP site of the enzyme. An extensive study of the effects of substitution around this template has been carried out, which has identified substituents which lead to improvements in potency and selectivity for Wee1. While retention of the maleimide ring and pendant 4-phenyl group is necessary for potency, replacement of the carbazole nitrogen by oxygen is well tolerated and results in improved Wee1 selectivity against the related checkpoint kinase Chk1. Wee1 potency and selectivity are also enhanced by the incorporation of lipophilic functionality at the 2'-position of the 4-phenyl ring, and Wee1 selectivity against Chk1 is favored by C3-C5 alkyl substitution of the carbazole nitrogen. These studies provide a basis for the design of active analogues of the pyrrolocarbazole lead with improved physical properties.

  DOI：

  10.1021/jm0512591
• 作为产物：
  描述：

  9-methoxy-4-phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione 在 吡啶盐酸盐 作用下， 反应 0.42h， 以78%的产率得到PD 47824
  参考文献：
  名称：

  4-Phenylpyrrolo[3,4-c]carbazole-1,3(2H,6H)-dione Inhibitors of the Checkpoint Kinase Wee1. Structure−Activity Relationships for Chromophore Modification and Phenyl Ring Substitution

  摘要：

  High-throughput screening has identified a novel class of inhibitors of the checkpoint kinase Wee1, which have potential for use in cancer chemotherapy. These inhibitors are based on a 4-phenylpyrrolo[3,4-c]carbazole- 1,3(2H,6H)-dione template and have been shown by X-ray crystallography to bind at the ATP site of the enzyme. An extensive study of the effects of substitution around this template has been carried out, which has identified substituents which lead to improvements in potency and selectivity for Wee1. While retention of the maleimide ring and pendant 4-phenyl group is necessary for potency, replacement of the carbazole nitrogen by oxygen is well tolerated and results in improved Wee1 selectivity against the related checkpoint kinase Chk1. Wee1 potency and selectivity are also enhanced by the incorporation of lipophilic functionality at the 2'-position of the 4-phenyl ring, and Wee1 selectivity against Chk1 is favored by C3-C5 alkyl substitution of the carbazole nitrogen. These studies provide a basis for the design of active analogues of the pyrrolocarbazole lead with improved physical properties.

  DOI：

  10.1021/jm0512591

文献信息

• Inhibitors of checkpoint kinases (Wee1 and Chk1)
  申请人：Pfizer Inc

  公开号：US07094798B1

  公开（公告）日：2006-08-22

  This invention relates to pyrrolocarbazole derivatives according formula I wherein R1, R2, R7, R8, R9, X and Y are as defined in the specification wherein said derivatives specifically inhibit one or both of the checkpoint kinases Wee1 and Chk1

  本发明涉及公式I中的吡咯烷并咔唑衍生物，其中R1、R2、R7、R8、R9、X和Y如规范中所定义，其中这些衍生物特异性抑制检查点激酶Wee1和Chk1中的一个或两个。
• PROGNOSTIC BIOMARKER FOR CANCER
  申请人：Universitat Autònoma de Barcelona

  公开号：EP3231875A1

  公开（公告）日：2017-10-18

  The invention relates to an in vitro method for determining the prognosis of a patient suffering from cancer, wherein the cancer is not hepatocarcinoma, based on CDK5RAP3 gene expression levels. The invention also relates to in vitro methods for predicting the clinical response of a patient suffering from cancer to a treatment with a DNA damaging agent, or for selecting a patient suffering from cancer for a therapy with a DNA damaging agent or for selecting a therapy for a patient suffering from cancer.

  本发明涉及一种根据CDK5RAP3基因表达水平确定癌症患者预后的体外方法，其中癌症不是肝癌。本发明还涉及一种体外方法，用于预测癌症患者对 DNA 损伤剂治疗的临床反应，或用于选择癌症患者接受 DNA 损伤剂治疗，或用于选择癌症患者的治疗方法。
• Neurofibromatoses therapeutic agents and screening for same
  申请人：Fernandez-Valle Cristina

  公开号：US10105351B2

  公开（公告）日：2018-10-23

  Disclosed herein are methods of treating a patient at risk of developing or having a neurofibromatosis or a sporadic schwannoma. In exemplary embodiments, the method involves administering to a subject in need an effective amount of a modulator of a target related to neurofibromatosis. Also disclosed are screening assays involving the implementation of Merlin-null Schwann cells, and to compounds identified using same.

  本文公开了治疗有患神经纤维瘤病或散发性分裂瘤风险的患者的方法。在示例性实施方案中，该方法涉及向有需要的受试者施用有效量的神经纤维瘤病相关靶点的调节剂。还公开了涉及实施Merlin-null许旺细胞的筛选试验，以及利用这些试验鉴定的化合物。
• Methods for identifying therapeutic targets and treating monitoring cancers
  申请人：Fred Hutchinson Cancer Research Center

  公开号：US10676746B2

  公开（公告）日：2020-06-09

  The present invention provides methods for treating cancers having a mutation in one or more tumor suppressor genes, comprising providing to a subject in need thereof an inhibitor of a kinase, as well as related methods and compositions.

  本发明提供了治疗一种或多种肿瘤抑制基因发生突变的癌症的方法，包括向有需要的受试者提供激酶抑制剂以及相关的方法和组合物。
• Modified Wee1, crystals of peptide: inhibitor complexes containing such modified Wee1, and methods of use thereof
  申请人：Baker Neill Edward

  公开号：US20050037476A1

  公开（公告）日：2005-02-17

  Modified Wee1 peptides, polynucleotides encoding those peptides, and methods for purifying the peptides and crystallizing them as peptide: inhibitor complexes have been discovered. The three-dimensional structure of Wee1, including the ATP substrate binding site, and uses of this information in the design and screening of compounds that may associate with Wee1, or peptides structurally related thereto, have also been discovered.

  已经发现了修饰的 Wee1 肽、编码这些肽的多核苷酸以及纯化这些肽并将其结晶为肽：抑制剂复合物的方法。此外，还发现了 Wee1 的三维结构，包括 ATP 底物结合位点，以及利用这些信息设计和筛选可能与 Wee1 结合的化合物或与之结构相关的多肽的方法。