2-(3,5-dichloro-4-hydroxyphenylamino)benzoic acid

• 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: 2-(3,5-dichloro-4-hydroxyphenylamino)benzoic acid
• 英文别名: 2-[(3,5-Dichloro-4-Hydroxyphenyl)amino]benzoic Acid；2-(3,5-dichloro-4-hydroxyanilino)benzoic acid
• 化学式: C₁₃H₉Cl₂NO₃
• 分子量: 298.125
• InChiKey: AKTRZQGZDAYEOG-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.8
• 重原子数：
  19
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  69.6
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  邻溴苯甲酸甲酯 在 palladium on activated charcoal lithium hydroxide 、 tris-(dibenzylideneacetone)dipalladium(0) 、 氢气 、 caesium carbonate 、 (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl 作用下， 以 四氢呋喃 、 甲醇 、 乙酸乙酯 、 甲苯 为溶剂， 反应 48.0h， 生成 2-(3,5-dichloro-4-hydroxyphenylamino)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

文献信息

• Identification of stabilizers of multimeric proteins
  申请人：The Board of Trustees of the Leland Stanford Junior University

  公开号：US10039726B2

  公开（公告）日：2018-08-07

  Disclosed herein are compounds and compositions thereof which find use in increasing stability of TTR tetramers reducing its tendency to misfold and form aggregates. Also provided herein are methods for using these compounds and compositions for increasing stability of TTR and therby decreasing aggegate formation by TTR. Also disclosed herein are methods to screen for candidate compounds that increase stability of TTR. Also disclosed herein are heterobifunctional compounds that include a TTR binding compound connected to a targeting moiety via a linker, for use in disrupting PP is of a target protein.

  本文公开的化合物及其组合物可用于提高 TTR 四聚体的稳定性，降低其折叠错误和形成聚集体的倾向。本文还提供了使用这些化合物和组合物提高 TTR 的稳定性并从而减少 TTR 形成聚集体的方法。本文还公开了筛选提高 TTR 稳定性的候选化合物的方法。本文还公开了杂多功能化合物，其中包括通过连接体与靶向分子连接的 TTR 结合化合物，用于破坏靶蛋白的 PP。
• COMPOUND AND USE THEREOF IN THE TREATMENT OF AMYLOIDOSIS
  申请人：Pentraxin Therapeutics Limited

  公开号：EP2203167A1

  公开（公告）日：2010-07-07
• Identification of Stabilizers of Multimeric Proteins
  申请人：The Board of Trustees of the Leland Stanford Junior University

  公开号：US20190054040A1

  公开（公告）日：2019-02-21

  Disclosed herein are compounds and compositions thereof which find use in increasing stability of TTR tetramers reducing its tendency to misfold and form aggregates. Also provided herein are methods for using these compounds and compositions for increasing stability of TTR and thereby decreasing aggregate formation by TTR. Also disclosed herein are methods to screen for candidate compounds that increase stability of TTR. Also disclosed herein are heterobifunctional compounds that include a TTR binding compound connected to a targeting moiety via a linker, for use in disrupting PPis of a target protein.
• [EN] COMPOUND AND USE THEREOF IN THE TREATMENT OF AMYLOIDOSIS<br/>[FR] COMPOSÉ ET SON UTILISATION POUR LE TRAITEMENT D'UNE AMYLOSE
  申请人：PENTRAXIN THERAPEUTICS LTD

  公开号：WO2009040405A1

  公开（公告）日：2009-04-02

  Agent for stabilising the tetrameric form of transthyretin, which comprises a compound of the general formula (I) or a pharmaceutically acceptable salt, ester or prodrug thereof: wherein: each Y is independently a direct bond or -CH2-; each X is independently -NH-, -O-, -S-, -CH2-, -NR-, -CO-, -CONH-, -CONR-, -C=N-O-, - NHCO-, -NRCO-, -O-N=C-, -SO-, -SO2- or a direct bond, wherein each of R1, R2, R3 and R4 is independently F, Cl, Br, I, CF3, O CF3, R', OR', NR'R', SOR' or SO2R', wherein R and R' are each independently C1-C3 alkyl which is straight or branched chain or cyclic optionally substituted by one or more halogen atoms; and each m, n, p and q is independently 0 to 4, wherein m+n+p+q>0; and wherein the linker is a linear or branched chain of 7 to 13 carbon atoms in which one or more of the carbon atoms are optionally replaced by a heteroatom, wherein the said chain is unsubstituted or substituted by one or more groups comprising halogen, O, or N atoms, or OH, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl or C1-C3 alkoxy.
• Kinetic Stabilization of an Oligomeric Protein by a Single Ligand Binding Event
  作者：R. Luke Wiseman、Steven M. Johnson、Matthew S. Kelker、Ted Foss、Ian A. Wilson、Jeffery W. Kelly

  DOI：10.1021/ja042929f

  日期：2005.4.1

  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.