Benzoic acid 2-[2-(2-{2-[2-(2-acetylsulfanyl-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethyl ester | 851961-96-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: Benzoic acid 2-[2-(2-{2-[2-(2-acetylsulfanyl-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethyl ester
• CAS: 851961-96-1
• 化学式: C₂₁H₃₂O₈S
• 分子量: 444.546
• InChiKey: IKLRFLWXVPPFNA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.21
• 重原子数：
  30.0
• 可旋转键数：
  19.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  89.52
• 氢给体数：
  0.0
• 氢受体数：
  9.0

反应信息

• 作为反应物：
  描述：

  Benzoic acid 2-[2-(2-{2-[2-(2-acetylsulfanyl-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethyl ester 在 偶氮二甲酸二异丙酯 、 sodium methylate 、 三苯基膦 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 6.0h， 生成 2-[3,5-Dichloro-4-(2-{2-[2-(2-{2-[2-(pyridin-2-yldisulfanyl)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethoxy}-ethoxy)-phenylamino]-benzoic acid
  参考文献：
  名称：

  Kinetic Stabilization of an Oligomeric Protein by a Single Ligand Binding Event

  摘要：

  Protein native state stabilization imposed by small molecule binding is an attractive strategy to prevent the misfolding and misassembly processes associated with amyloid diseases. Transthyretin (TTR) amyloidogenesis requires rate-limiting tetramer dissociation before misassembly of a partially denatured monomer ensues. Selective stabilization of the native TTR tetramer over the dissociative transition state by small molecule binding to both thyroxine binding sites raises the kinetic barrier of tetramer dissociation, preventing amyloidogenesis. Assessing the amyloidogenicity of a TTR tetramer having only one amyloidogenesis inhibitor (1) bound is challenging because the two small molecule binding constants are generally not distinct enough to allow for the exclusive formation of (TTRI)-I-. in solution to the exclusion of (TTRI2)-I-. and unliganded TTR. Herein, we report a method to tether one fibril formation inhibitor to TTR by disulfide bond formation. Occupancy of only one of the two thyroxine binding sites is sufficient to inhibit tetramer dissociation in 6.0 M urea and amyloidogenesis under acidic conditions by imposing kinetic stabilization on the entire tetramer. The sufficiency of single occupancy for stabilizing the native state of TTR provides the incentive to search for compounds displaying striking negative binding cooperativity (e.g., K-d1 in nanomolar range and K-d2 in the micromolar to millimolar range), enabling lower doses of inhibitor to be employed in the clinic, mitigating potential side effects.

  DOI：

  10.1021/ja042929f
• 作为产物：
  描述：

  六甘醇 在 吡啶 、 N-溴代丁二酰亚胺(NBS) 、 sodium hydride 、 三苯基膦 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 25.0h， 生成 Benzoic acid 2-[2-(2-{2-[2-(2-acetylsulfanyl-ethoxy)-ethoxy]-ethoxy}-ethoxy)-ethoxy]-ethyl ester
  参考文献：
  名称：

  Kinetic Stabilization of an Oligomeric Protein by a Single Ligand Binding Event

  摘要：

  Protein native state stabilization imposed by small molecule binding is an attractive strategy to prevent the misfolding and misassembly processes associated with amyloid diseases. Transthyretin (TTR) amyloidogenesis requires rate-limiting tetramer dissociation before misassembly of a partially denatured monomer ensues. Selective stabilization of the native TTR tetramer over the dissociative transition state by small molecule binding to both thyroxine binding sites raises the kinetic barrier of tetramer dissociation, preventing amyloidogenesis. Assessing the amyloidogenicity of a TTR tetramer having only one amyloidogenesis inhibitor (1) bound is challenging because the two small molecule binding constants are generally not distinct enough to allow for the exclusive formation of (TTRI)-I-. in solution to the exclusion of (TTRI2)-I-. and unliganded TTR. Herein, we report a method to tether one fibril formation inhibitor to TTR by disulfide bond formation. Occupancy of only one of the two thyroxine binding sites is sufficient to inhibit tetramer dissociation in 6.0 M urea and amyloidogenesis under acidic conditions by imposing kinetic stabilization on the entire tetramer. The sufficiency of single occupancy for stabilizing the native state of TTR provides the incentive to search for compounds displaying striking negative binding cooperativity (e.g., K-d1 in nanomolar range and K-d2 in the micromolar to millimolar range), enabling lower doses of inhibitor to be employed in the clinic, mitigating potential side effects.

  DOI：

  10.1021/ja042929f