3-(4-((2,4-dichlorophenyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: 3-(4-((2,4-dichlorophenyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
• 英文别名: 3-[7-(2,4-dichlorophenyl)sulfanyl-3-oxo-1H-isoindol-2-yl]piperidine-2,6-dione
• 化学式: C₁₉H₁₄Cl₂N₂O₃S
• 分子量: 421.304
• InChiKey: AIMXHTQUPODNTD-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  91.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  2,4-二氯苯硫酚 、 来那度胺 在 tris(2,2'-bipyridyl)ruthenium dichloride 、 对甲苯磺酸 、 亚硝酸特丁酯 作用下， 反应 0.08h， 以53%的产率得到3-(4-((2,4-dichlorophenyl)thio)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
  参考文献：
  名称：

  Design, synthesis and biological evaluation of thioether-containing lenalidomide and pomalidomide derivatives with anti-multiple myeloma activity

  摘要：

  Lenalidomide and its analogs are well-known for treating multiple myeloma. In this work, designed sulfide-modified lenalidomide and pomalidomide were synthesized and evaluated. The anti-proliferative activity against MM.1S cell line of 3ak (IC₅₀ = 79 nM) was similar to lenalidomide (IC₅₀ = 81 nM). Compared to benzylic thioether substituted lenalidomide 3a, the half-live (T_1/2) of 4-F-phenyl-thioether analogs 3ak in human liver microsomes was promoted from 3 min to 416.7 min. The corresponding metabolic factor of 3ak was increased from 2.8% to 79.5%, which was slightly lower than lenalidomide (91.5%). Moreover, the IKZF1 degradation of 3y and 3ak was well related with corresponding IC₅₀ values, which suggested the IKZF1 degradation efficiency is correlated to the responses of MM1. S cells. Furthermore, the oral administration of compounds 3y and 3ak at dosages of 60 mg/kg could delay tumor growth in female CB-17 SCID mice. This research helped to prompt the stability of thioether lenalidomide analogs, which paved the way for developing better molecules for treating multiple myeloma.

  DOI：

  10.1016/j.ejmech.2020.112912

文献信息

• Design, synthesis and biological evaluation of thioether-containing lenalidomide and pomalidomide derivatives with anti-multiple myeloma activity
  作者：Yuhong Wang、Tian Mi、Yiming Li、Weijuan Kan、Gaoya Xu、Jingya Li、Yubo Zhou、Jia Li、Xuefeng Jiang

  DOI：10.1016/j.ejmech.2020.112912

  日期：2021.1

  Lenalidomide and its analogs are well-known for treating multiple myeloma. In this work, designed sulfide-modified lenalidomide and pomalidomide were synthesized and evaluated. The anti-proliferative activity against MM.1S cell line of 3ak (IC₅₀ = 79 nM) was similar to lenalidomide (IC₅₀ = 81 nM). Compared to benzylic thioether substituted lenalidomide 3a, the half-live (T_1/2) of 4-F-phenyl-thioether analogs 3ak in human liver microsomes was promoted from 3 min to 416.7 min. The corresponding metabolic factor of 3ak was increased from 2.8% to 79.5%, which was slightly lower than lenalidomide (91.5%). Moreover, the IKZF1 degradation of 3y and 3ak was well related with corresponding IC₅₀ values, which suggested the IKZF1 degradation efficiency is correlated to the responses of MM1. S cells. Furthermore, the oral administration of compounds 3y and 3ak at dosages of 60 mg/kg could delay tumor growth in female CB-17 SCID mice. This research helped to prompt the stability of thioether lenalidomide analogs, which paved the way for developing better molecules for treating multiple myeloma.