(1''R,2''S,2'R,3'R,3S,4'R)-6-chloro-4'-(3-chlorophenyl)-1'-(2-hydroxy-1,2-diphenylethyl)-2'-isobutyl-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid dimethylamide | 860797-93-9

• 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)-1'-(2-hydroxy-1,2-diphenylethyl)-2'-isobutyl-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)-1'-(2-hydroxy-1,2-diphenyl-ethyl)-2'-isobutyl-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)-1'-[(1R,2S)-2-hydroxy-1,2-diphenylethyl]-N,N-dimethyl-5'-(2-methylpropyl)-2-oxospiro[1H-indole-3,4'-pyrrolidine]-2'-carboxamide
• CAS: 860797-93-9
• 化学式: C₃₈H₃₉Cl₂N₃O₃
• 分子量: 656.652
• InChiKey: MXXBWUNNNDKPGE-LTLHWJIPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.1
• 重原子数：
  46
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.32
• 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)-1'-(2-hydroxy-1,2-diphenylethyl)-2'-isobutyl-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid dimethylamide 在 lead(IV) acetate 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 生成 (2'R,3S,4'R,5'R)-6-chloro-4'-(3-chlorophenyl)-2'-isobutyl-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
• 作为产物：
  描述：

  6-氯氧化吲哚 在 potassium fluoride on basic alumina 、 4 A molecular sieve 作用下， 以 四氢呋喃 、 二氯甲烷 、 甲苯 、 乙腈 为溶剂， 反应 5.17h， 生成 (1''R,2''S,2'R,3'R,3S,4'R)-6-chloro-4'-(3-chlorophenyl)-1'-(2-hydroxy-1,2-diphenylethyl)-2'-isobutyl-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

• 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。
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