(3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-N-(2-morpholinoethyl)-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide trifluoroacetate | 1410737-90-4

• 英文名称: (3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-N-(2-morpholinoethyl)-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide trifluoroacetate
• CAS: 1410737-90-4
• 化学式: C₂HF₃O₂*C₂₉H₃₃Cl₂FN₄O₃
• 分子量: 689.534
• InChiKey: WTAFLWBKAVURGU-CRXMCIAMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.86
• 重原子数：
  46.0
• 可旋转键数：
  5.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  120.0
• 氢给体数：
  4.0
• 氢受体数：
  6.0

反应信息

• 作为产物：
  描述：

  在 ammonium cerium (IV) nitrate 、 三氟乙酸 作用下， 以 甲醇 、 水 、 乙腈 为溶剂， 反应 24.08h， 生成 (3'R,4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-N-(2-morpholinoethyl)-2''-oxodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indoline]-5'-carboxamide trifluoroacetate
  参考文献：
  名称：

  Design of Chemically Stable, Potent, and Efficacious MDM2 Inhibitors That Exploit the Retro-Mannich Ring-Opening-Cyclization Reaction Mechanism in Spiro-oxindoles

  摘要：

  Inhibition of the MDM2-p53 protein-protein interaction is being actively pursued as a new anticancer therapeutic strategy, and spiro-oxindoles have been designed as a class of potent and efficacious small-molecule inhibitors of this interaction (MDM2 inhibitors). Our previous study showed that some of our first-generation spiro-oxindoles undergo a reversible ring-opening-cyclization reaction that, from a single compound in protic solution, results in an equilibrium mixture of four diastereoisomers. By exploiting the ring-opening-cyclization reaction mechanism, we have designed and synthesized a series of second-generation spiro-oxindoles with symmetrical pyrrolidine C2 substitution. These compounds undergo a rapid and irreversible conversion to a single, stable diastereoisomer. Our study has yielded compound 31 (MI-1061), which binds to MDM2 with K-i = 0.16 nM, shows excellent chemical stability, and achieves tumor regression in the SJSA-1 xenograft tumor model in mice.

  DOI：

  10.1021/jm501541j