10-(phenyl)phenoxazine-4,6-dicarboxylic acid | 102160-09-8

• 分子结构分类: 有机化合物 - 有机氮化合物
• 英文名称: 10-(phenyl)phenoxazine-4,6-dicarboxylic acid
• 英文别名: 10-phenyl-phenoxazine-4,6-dicarboxylic acid；10-Phenyl-phenoxazin-4,6-dicarbonsaeure；10-Phenylphenoxazine-4,6-dicarboxylic acid；10-phenylphenoxazine-4,6-dicarboxylic acid
• CAS: 102160-09-8
• 化学式: C₂₀H₁₃NO₅
• 分子量: 347.327
• InChiKey: WLVQAYUUFLSCAC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.8
• 重原子数：
  26
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.0
• 拓扑面积：
  87.1
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  吩噁嗪 在 lithium hydroxide 、 正丁基锂 、 tris(dibenzylideneacetone)dipalladium (0) 、 四丁基氟化铵 、 sodium hydride 、 caesium carbonate 、 R-(+)-1,1'-联萘-2,2'-双二苯膦 作用下， 以 四氢呋喃 、 甲醇 、 甲苯 、 Petroleum ether 、 苯 为溶剂， 20.0~100.0 ℃ 、103.42 kPa 条件下， 反应 48.17h， 生成 10-(phenyl)phenoxazine-4,6-dicarboxylic acid
  参考文献：
  名称：

  Structure-Based Design of N-Phenyl Phenoxazine Transthyretin Amyloid Fibril Inhibitors

  摘要：

  Starting with the published 2.0 Angstrom X-ray crystal structure of the transthyretin (flufenamic acid)(2) complex, a simple structure-based ligand design strategy was employed to conceive of N-phenyl phenoxazine transthyretin (TTR) amyloid fibril inhibitors. Fifteen N-phenyl phenoxazines were chemically synthesized and evaluated using a quantitative amyloid fibril assay in vitro. The structure of one of the two most active phenoxazines, 4, bound to TTR was solved to a resolution of 1.9 Angstrom to understand the structural basis of its efficacy. N-phenyl phenoxazine 4 binds similar to the orientation anticipated, although not as deeply into the channel as expected. Like flufenamic acid. 4 mediates binding-induced conformational changes that enable intersubunit H-bonding in tetrameric TTR which may be important Tor preventing fibril formation. Analytical ultracentrifugation analysis demonstrates that 4 blocks the first step of TTR amyloid fibril formation, that is, tetramer dissociation to the alternatively folded amyloidogenic monomer. Isothermal titration calorimetry was used to determine the binding constants of 4 to TTR and to dissect the enthalpy and entropy contributions associated with ligand binding. Phenoxazine 4 exhibits binding and inhibitor efficacy against WT TTR that is very similar to that of flufenamic acid, unlike the situation with the inhibition of L55P fibril formation where 4 is superior to Flu as an inhibitor but not as a binder. It is clear that 4 functions in part by stabilizing the normally folded tetramer through formation of the TTR (4)2 complex, which in turn increases the activation energy for tetramer dissociation. The data also suggest that 4 destabilizes the transition state associated with TTR dissociation to the monomeric amyloidogenic intermediate. Future biophysical studies, including kinetic measurements, are needed to understand the exact mechanism(s) of the action of 4.

  DOI：

  10.1021/ja993309v

文献信息

• The Metalation of Phenoxazine and Some of its Derivatives¹
  作者：Henry Gilman、Leonard O. Moore

  DOI：10.1021/ja01542a040

  日期：1958.5

  Phenox azine, 10-ethyl-, and 10-phenylphenoxazine are metalated by n- butyllithium to give what probably are 4-substituted carboxylic acids. Attempts to prove the structures by interconversion of the acids were not successful. 10- Ethylphenoxazine-8-carboxylic acid and 10-(4-carboxyphenyl)-phenoxnzine were prepared by a halogen-metal interconversion reaction, which established these structures. (auth)

  吩恶嗪、10-乙基-和10-苯基吩恶嗪被正丁基锂金属化，得到可能是4-取代的羧酸。通过酸的相互转化来证明结构的尝试没有成功。10-乙基吩恶嗪-8-羧酸和10-(4-羧基苯基)-吩恶嗪通过卤素-金属互变反应制备，建立了这些结构。（授权）