4-{4,4-dimethyl-2,5-dioxo-3-[2-(2-piperazin-1-ylethoxy)ethoxy]imidazolidin-1-yl}-2-trifluoromethylbenzonitrile | 636595-88-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑烷类
• 英文名称: 4-{4,4-dimethyl-2,5-dioxo-3-[2-(2-piperazin-1-ylethoxy)ethoxy]imidazolidin-1-yl}-2-trifluoromethylbenzonitrile
• 英文别名: 4-[4,4-Dimethyl-2,5-dioxo-3-[2-(2-piperazin-1-ylethoxy)ethyl]imidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile
• CAS: 636595-88-5
• 化学式: C₂₁H₂₆F₃N₅O₃
• 分子量: 453.464
• InChiKey: LXBGENSSRRZNAI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.57
• 拓扑面积：
  88.9
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  5-(2-bromoethoxymethyl)-2-hydroxybenzamide 、 4-{4,4-dimethyl-2,5-dioxo-3-[2-(2-piperazin-1-ylethoxy)ethoxy]imidazolidin-1-yl}-2-trifluoromethylbenzonitrile 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 20.0h， 以83%的产率得到5-{2-[4-(2-{2-[3-(4-cyano-3-trifluoromethyl-phenyl)-5,5-dimethyl-2,4-dioxo-imidazolidin-1-yl]-ethoxy}-ethyl)-piperazine-1-yl]-ethoxymethyl}-2-hydroxy-benzamide
  参考文献：
  名称：

  Rational Design and Synthesis of Androgen Receptor-Targeted Nonsteroidal Anti-Androgen Ligands for the Tumor-Specific Delivery of a Doxorubicin−Formaldehyde Conjugate

  摘要：

  The synthesis and preliminary evaluation of a doxorubicin-formaldehyde conjugate tethered to the nonsteroidal antiandrogen, cyanonilutamide (RU 56279), for the treatment of prostate cancer are reported. The relative ability of the targeting group to bind to the human androgen receptor was studied as a function of tether. The tether served to attach the antiandrogen to the doxorubicin-formaldehyde conjugate via an N-Mannich base of a salicylamide derivative. The salicylamide was selected to serve as a trigger release mechanism to separate the doxorubicin-formaldehyde conjugate from the targeting group after it has bound to the androgen receptor. The remaining part of the tether consisted of a linear group that spanned from the 5-position of the salicylamide to the X-position of cyanonilutamide. The structures explored for the linear region of the tether were derivatives of di(ethylene glycol), tri(ethylene glycol), N,N'-disubstituted-piperazine, and 2-butyne-1,4-diol. Relative binding affinity of the tethers bound to the targeting group for human androgen receptor were measured using a 3 H-Mibolerone competition assay and varied from 18% of nilutamide binding for the butynediol-based linear region to less than 1% for one of the piperazine derivatives. The complete targeted drug with the butynediol-based linear region has a relative binding affinity of 10%. This relative binding affinity is encouraging in light of the cocrystal structure of human androgen receptor ligand binding domain bound to the steroid Metribolone which predicts very limited space for a tether connecting the antiandrogen on the inside to the cytotoxin on the outside.

  DOI：

  10.1021/jm0303305
• 作为产物：
  描述：

  4-(4,4-二甲基-2,5-二氧代咪唑烷-1-基)-2-三氟甲基苯甲腈 在 sodium hydride 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 4-{4,4-dimethyl-2,5-dioxo-3-[2-(2-piperazin-1-ylethoxy)ethoxy]imidazolidin-1-yl}-2-trifluoromethylbenzonitrile
  参考文献：
  名称：

  Rational Design and Synthesis of Androgen Receptor-Targeted Nonsteroidal Anti-Androgen Ligands for the Tumor-Specific Delivery of a Doxorubicin−Formaldehyde Conjugate

  摘要：

  The synthesis and preliminary evaluation of a doxorubicin-formaldehyde conjugate tethered to the nonsteroidal antiandrogen, cyanonilutamide (RU 56279), for the treatment of prostate cancer are reported. The relative ability of the targeting group to bind to the human androgen receptor was studied as a function of tether. The tether served to attach the antiandrogen to the doxorubicin-formaldehyde conjugate via an N-Mannich base of a salicylamide derivative. The salicylamide was selected to serve as a trigger release mechanism to separate the doxorubicin-formaldehyde conjugate from the targeting group after it has bound to the androgen receptor. The remaining part of the tether consisted of a linear group that spanned from the 5-position of the salicylamide to the X-position of cyanonilutamide. The structures explored for the linear region of the tether were derivatives of di(ethylene glycol), tri(ethylene glycol), N,N'-disubstituted-piperazine, and 2-butyne-1,4-diol. Relative binding affinity of the tethers bound to the targeting group for human androgen receptor were measured using a 3 H-Mibolerone competition assay and varied from 18% of nilutamide binding for the butynediol-based linear region to less than 1% for one of the piperazine derivatives. The complete targeted drug with the butynediol-based linear region has a relative binding affinity of 10%. This relative binding affinity is encouraging in light of the cocrystal structure of human androgen receptor ligand binding domain bound to the steroid Metribolone which predicts very limited space for a tether connecting the antiandrogen on the inside to the cytotoxin on the outside.

  DOI：

  10.1021/jm0303305