1-hydroxydibenzofuran-4,6-dicarboxylic acid dimethyl ester | 853070-71-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并呋喃
• 英文名称: 1-hydroxydibenzofuran-4,6-dicarboxylic acid dimethyl ester
• 英文别名: 1-Hydroxy-dibenzofuran-4,6-dicarboxylic acid dimethyl ester；dimethyl 1-hydroxydibenzofuran-4,6-dicarboxylate
• CAS: 853070-71-0
• 化学式: C₁₆H₁₂O₆
• 分子量: 300.268
• InChiKey: YQYQKUOMGAAZJE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  86
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  1-hydroxydibenzofuran-4,6-dicarboxylic acid dimethyl ester 在 吡啶 、 四(三苯基膦)钯 、 sodium carbonate 、 lithium chloride 作用下， 以 甲醇 、 甲苯 为溶剂， 反应 12.0h， 生成 1-(2-chlorophenyl)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
• 作为产物：
  描述：

  1-羟基二苯并呋喃 在 4-二甲氨基吡啶 、 四甲基乙二胺 、 四丁基氟化铵 、 仲丁基锂 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 正己烷 、 二氯甲烷 、 环己烷 、 苯 为溶剂， 反应 1.5h， 生成 1-hydroxydibenzofuran-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

文献信息

• Transthyretin stabilization
  申请人：Kelly W. Jeffery

  公开号：US20050261365A1

  公开（公告）日：2005-11-24

  Dibenzofuran-4,6-dicarboxylic acid core structures having an aromatic substituent appended onto the at the C1 position using three different types of linkages are disclosed herein and shown to afford exceptional amyloidogenesis inhibitors that display increased affinity and greatly increased binding selectivity to TTR over all the other plasma proteins, relative to lead compound 1. It is further disclosed herein that these compounds function by imposing kinetic stabilization on the TTR tetramer.

  本文披露了具有芳香族取代基的二苯并呋喃-4,6-二羧酸核结构，该取代基附加在C1位置上，使用三种不同类型的连接，显示出优异的淀粉样生成抑制剂，这些抑制剂显示出相对于引物化合物1，具有更高的亲和力和大大增加的结合选择性，相对于所有其他血浆蛋白。进一步披露了这些化合物通过对TTR四聚体施加动力学稳定来发挥作用。
• Transthyretin Stabilization
  申请人：Kelly Jeffery W.

  公开号：US20080319175A1

  公开（公告）日：2008-12-25

  Dibenzofuran-4,6-dicarboxylic acid core structures having an aromatic substituent appended onto the at the C1 position using three different types of linkages are disclosed herein and shown to afford exceptional amyloidogenesis inhibitors that display increased affinity and greatly increased binding selectivity to TTR over all the other plasma proteins, relative to lead compound 1. It is further disclosed herein that these compounds function by imposing kinetic stabilization on the TTR tetramer.

  本文披露了在Dibenzofuran-4,6-dicarboxylic acid核心结构上附加芳香基取代物的三种不同类型的连接方式，这些取代物被证明是出色的淀粉样生成抑制剂，相对于引领化合物1，它们显示出增加的亲和力和极大的选择性结合TTR而非其他所有血浆蛋白质。此外，本文还披露了这些化合物通过对TTR四聚体施加动力学稳定作用来发挥作用。
• TRANSTHYRETIN STABILIZATION
  申请人：THE SCRIPPS RESEARCH INSTITUTE

  公开号：EP1755585A1

  公开（公告）日：2007-02-28
• EP1755585A4
  申请人：——

  公开号：EP1755585A4

  公开（公告）日：2009-04-01
• [EN] TRANSTHYRETIN STABILIZATION<br/>[FR] STABILISATION DE LA TRANSTHYRETINE
  申请人：SCRIPPS RESEARCH INST

  公开号：WO2005112913A1

  公开（公告）日：2005-12-01

  Dibenzοfuran-4,6-dicarboxylic acid core structures having an aromatic substituent appended onto the at the C1 position using three different types of linkages are disclosed herein and shown to afford exceptional amyloidogenesis inhibitors that display increased affinity and greatly increased binding selectivity to TTR over all the other plasma proteins, relative to lead compound 1. It is further disclosed herein that these compounds function by imposing kinetic stabilization on the TTR tetramer.