1-(3-chloro-phenylamino)dibenzofuran-4,6-dicarboxylic acid dimethyl ester | 853070-76-5

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: 1-(3-chloro-phenylamino)dibenzofuran-4,6-dicarboxylic acid dimethyl ester
• CAS: 853070-76-5
• 化学式: C₂₂H₁₆ClNO₅
• 分子量: 409.826
• InChiKey: UQUOJKGWSKQSCI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.56
• 重原子数：
  29.0
• 可旋转键数：
  4.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  77.77
• 氢给体数：
  1.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  1-(3-chloro-phenylamino)dibenzofuran-4,6-dicarboxylic acid dimethyl ester 在 lithium hydroxide 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 以98%的产率得到1-(3-chlorophenylamino)dibenzofuran-4,6-dicarboxylic acid
  参考文献：
  名称：

  Potent and Selective Structure-Based Dibenzofuran Inhibitors of Transthyretin Amyloidogenesis:  Kinetic Stabilization of the Native State

  摘要：

  Transthyretin (TTR) amyloidogenesis requires rate-limiting tetramer dissociation and partial monomer denaturation to produce a misassembly competent species. This process has been followed by turbidity to identify transthyretin amyloidogenesis inhibitors including dibenzofuran-4,6-dicarboxylic acid (1). An X-ray cocrystal structure of TTR.1(2) reveals that it only utilizes the outer portion of the two thyroxine binding pockets to bind to and inhibit TTR amyloidogenesis. Herein, structure-based design was employed to append aryl substituents at C1 of the dibenzofuran ring to complement the unused inner portion of the thyroxine binding pockets. Twenty-eight amyloidogenesis inhibitors of increased potency and dramatically increased plasma TTR binding selectivity resulted. These function by imposing kinetic stabilization on the native tetrameric structure of TTR, creating a barrier that is insurmountable under physiological conditions. Since kinetic stabilization of the TTR native state by interallelic trans suppression is known to ameliorate disease, there is reason to be optimistic that the dibenzofuran-based inhibitors will do the same. Preventing the onset of amyloidogenesis is the most conservative strategy to intervene clinically, as it remains unclear which of the TTR misassembly intermediates results in toxicity. The exceptional binding selectivity enables these inhibitors to occupy the thyroxine binding site(s) in a complex biological fluid such as blood plasma, required for inhibition of amyloidogenesis in humans. It is now established that the dibenzofuran-based amyloidogenesis inhibitors have high selectivity, affinity, and efficacy and are thus excellent candidates for further pharmacologic evaluation.

  DOI：

  10.1021/ja044351f
• 作为产物：
  描述：

  1-hydroxydibenzofuran-4,6-dicarboxylic acid dimethyl ester 在 吡啶 、 palladium dibenzylidene acetone 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 作用下， 以 甲苯 为溶剂， 反应 36.0h， 生成 1-(3-chloro-phenylamino)dibenzofuran-4,6-dicarboxylic acid dimethyl ester
  参考文献：
  名称：

  Potent and Selective Structure-Based Dibenzofuran Inhibitors of Transthyretin Amyloidogenesis:  Kinetic Stabilization of the Native State

  摘要：

  Transthyretin (TTR) amyloidogenesis requires rate-limiting tetramer dissociation and partial monomer denaturation to produce a misassembly competent species. This process has been followed by turbidity to identify transthyretin amyloidogenesis inhibitors including dibenzofuran-4,6-dicarboxylic acid (1). An X-ray cocrystal structure of TTR.1(2) reveals that it only utilizes the outer portion of the two thyroxine binding pockets to bind to and inhibit TTR amyloidogenesis. Herein, structure-based design was employed to append aryl substituents at C1 of the dibenzofuran ring to complement the unused inner portion of the thyroxine binding pockets. Twenty-eight amyloidogenesis inhibitors of increased potency and dramatically increased plasma TTR binding selectivity resulted. These function by imposing kinetic stabilization on the native tetrameric structure of TTR, creating a barrier that is insurmountable under physiological conditions. Since kinetic stabilization of the TTR native state by interallelic trans suppression is known to ameliorate disease, there is reason to be optimistic that the dibenzofuran-based inhibitors will do the same. Preventing the onset of amyloidogenesis is the most conservative strategy to intervene clinically, as it remains unclear which of the TTR misassembly intermediates results in toxicity. The exceptional binding selectivity enables these inhibitors to occupy the thyroxine binding site(s) in a complex biological fluid such as blood plasma, required for inhibition of amyloidogenesis in humans. It is now established that the dibenzofuran-based amyloidogenesis inhibitors have high selectivity, affinity, and efficacy and are thus excellent candidates for further pharmacologic evaluation.

  DOI：

  10.1021/ja044351f