(1''R,2''S,2'R,3'R,3S,4'R)-6-chloro-4'-(3-chlorophenyl)-2'-(2,2-dimethylpropyl)-1'-(2-hydroxy-1,2-diphenylethyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid dimethylamide | 860797-95-1

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: (1''R,2''S,2'R,3'R,3S,4'R)-6-chloro-4'-(3-chlorophenyl)-2'-(2,2-dimethylpropyl)-1'-(2-hydroxy-1,2-diphenylethyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid dimethylamide
• 英文别名: (1''R,2''S,2'R,3S,4'R,5'R)-6-chloro-4'-(3-chloro-phenyl)-2'-(2,2-dimethyl-propyl)-1'-(2-hydroxy-1,2-diphenyl-ethyl)-2-oxo-1,2-dihydro-spiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid dimethylamide；(2'R,3S,3'R,5'R)-6-chloro-3'-(3-chlorophenyl)-5'-(2,2-dimethylpropyl)-1'-[(1R,2S)-2-hydroxy-1,2-diphenylethyl]-N,N-dimethyl-2-oxospiro[1H-indole-3,4'-pyrrolidine]-2'-carboxamide
• CAS: 860797-95-1
• 化学式: C₃₉H₄₁Cl₂N₃O₃
• 分子量: 670.679
• InChiKey: RPJIQUYEELCHGJ-MUNTWPFKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.5
• 重原子数：
  47
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  72.9
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (1''R,2''S,2'R,3'R,3S,4'R)-6-chloro-4'-(3-chlorophenyl)-2'-(2,2-dimethylpropyl)-1'-(2-hydroxy-1,2-diphenylethyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid dimethylamide 在 ammonium cerium (IV) nitrate 作用下， 以 水 、 乙腈 为溶剂， 反应 1.0h， 以50%的产率得到(2'R,3S,4'R,5'R)-6-chloro-4'-(3-chlorophenyl)-2-oxo-2'-(2,2-dimethylpropyl)-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid dimethylamide
  参考文献：
  名称：

  SPIRO-OXINDOLE MDM2 ANTAGONISTS

  摘要：

  本文提供了关于药物化学领域的化合物、组合物和方法。这里提供的化合物和组合物涉及螺环氧吲哚，其作为p53和MDM2相互作用的拮抗剂，并且它们作为治疗癌症和其他疾病的药物的用途。

  公开号：

  US20120122947A1
• 作为产物：
  描述：

  3,3-二甲基丁醛 在 4 A molecular sieve 作用下， 以 四氢呋喃 、 甲苯 为溶剂， 反应 5.0h， 生成 (1''R,2''S,2'R,3'R,3S,4'R)-6-chloro-4'-(3-chlorophenyl)-2'-(2,2-dimethylpropyl)-1'-(2-hydroxy-1,2-diphenylethyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid dimethylamide
  参考文献：
  名称：

  Structure-Based Design of Potent Non-Peptide MDM2 Inhibitors

  摘要：

  A successful structure-based design of a class of non-peptide small-molecule MDM2 inhibitors targeting the p53-MDM2 protein-protein interaction is reported. The most potent compound 1d binds to MDM2 protein with a Ki value of 86 nM and is 18 times more potent than a natural p53 peptide (residues 16-27). Compound 1d is potent in inhibition of cell growth in LNCaP prostate cancer cells with wild-type p53 and shows only a weak activity in PC-3 prostate cancer cells with a deleted p53. Importantly, 1d has a minimal toxicity to normal prostate epithelial cells. Our studies provide a convincing example that structure-based strategy can be employed to design highly potent, non-peptide, cell-permeable, small-molecule inhibitors to target protein-protein interaction, which remains a very challenging area in chemical biology and drug design.

  DOI：

  10.1021/ja051147z

文献信息

• Diastereomeric Spirooxindoles as Highly Potent and Efficacious MDM2 Inhibitors
  作者：Yujun Zhao、Liu Liu、Wei Sun、Jianfeng Lu、Donna McEachern、Xiaoqin, Li、Shanghai Yu、Denzil Bernard、Philippe Ochsenbein、Vincent Ferey、Jean-Christophe Carry、Jeffrey R. Deschamps、Duxin Sun、Shaomeng Wang

  DOI：10.1021/ja3125417

  日期：2013.5.15

  which affords four diastereomers from a single compound. Our biochemical binding data showed that the stereochemistry in this class of compounds has a major effect on their binding affinities to MDM2, with >100-fold difference between the most potent and the least potent stereoisomers. Our study has led to the identification of a set of highly potent MDM2 inhibitors with a stereochemistry that is different

  阻断 MDM2-p53 蛋白-蛋白相互作用的小分子抑制剂（MDM2 抑制剂）作为一种新的癌症治疗策略正受到强烈追捧。我们之前发表了一系列含有螺环吲哚的化合物作为一类新的 MDM2 小分子抑制剂。我们在此报告了这些螺吲哚中的一些的可逆开环环化反应，该反应从单个化合物提供四种非对映异构体。我们的生化结合数据表明，这类化合物的立体化学对其与 MDM2 的结合亲和力有主要影响，最强和最弱立体异构体之间的差异大于 100 倍。我们的研究已经确定了一组高效的 MDM2 抑制剂，其立体化学不同于我们之前报道的化合物。
• SMALL MOLECULE INHIBITORS OF MDM2 AND THE USES THEREOF
  申请人：Wang Shaomeng

  公开号：US20120101092A1

  公开（公告）日：2012-04-26

  The invention relates to small molecules which function as inhibitors of the interaction between p53 and MDM2. The invention also relates to the use of these compounds for inhibiting cell growth, inducing cell death, inducing cell cycle arrest and/or sensitizing cells to additional agent(s).

  本发明涉及小分子，其作为p53和MDM2相互作用的抑制剂。本发明还涉及使用这些化合物来抑制细胞生长，诱导细胞死亡，诱导细胞周期停滞和/或使细胞对其他药物更敏感。
• PROCESS FOR THE PREPARATION OF SMALL MOLECULE INHIBITORS OF MDM2 AND INTERMEDIATES USED THEREIN
  申请人：Wang Shaomeng

  公开号：US20130030173A1

  公开（公告）日：2013-01-31

  The invention relates to small molecules which function as inhibitors of the interaction between p53 and MDM2. The invention also relates to the use of these compounds for inhibiting cell growth, inducing cell death, inducing cell cycle arrest and/or sensitizing cells to additional agent(s).

  本发明涉及作为p53和MDM2相互作用抑制剂的小分子。本发明还涉及使用这些化合物来抑制细胞生长，诱导细胞死亡，诱导细胞周期阻滞和/或使细胞对其他药物敏感。
• US8088931B2
  申请人：——

  公开号：US8088931B2

  公开（公告）日：2012-01-03
• US8742121B2
  申请人：——

  公开号：US8742121B2

  公开（公告）日：2014-06-03