(E)-3-(2,4-bis(benzyloxy)phenyl)acrylic acid

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 肉桂酸及其衍生物
• 英文名称: (E)-3-(2,4-bis(benzyloxy)phenyl)acrylic acid
• 英文别名: (E)-3-(2,4-dibenzyloxyphenyl)prop-2-enoic acid；(E)-3-[2,4-bis(phenylmethoxy)phenyl]prop-2-enoic acid
• 化学式: C₂₃H₂₀O₄
• 分子量: 360.409
• InChiKey: QLCSCTDWFRAZMR-WYMLVPIESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.8
• 重原子数：
  27
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  55.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (E)-3-(2,4-bis(benzyloxy)phenyl)acrylic acid 在 N-甲基吗啉 、 三溴化硼 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 25.0h， 生成 (E)-3-(2,4-dihydroxyphenyl)-1-(piperidin-1-yl)prop-2-en-1-one
  参考文献：
  名称：

  肉桂酰胺衍生物的设计，合成及抗黑色素作用

  摘要：

  色素沉着障碍归因于酪氨酸酶可能产生过多的黑色素。因此，酪氨酸酶被认为是治疗与色素沉着过度有关的疾病的重要靶标。根据我们先前的发现，（E）-β-苯基-α，β-不饱和羰基支架可以在抑制酪氨酸酶活性方面发挥关键作用，而肉桂酸是具有支架结构的安全天然物质，据推测，适当的肉桂酸衍生物可表现出有效的酪氨酸酶抑制活性。因此，设计了十种肉桂酰胺，并以霍纳-埃蒙斯烯化为关键步骤合成了十种肉桂酰胺。肉桂酰胺4（抑制93.72％），9（抑制78.97％）和10具有2,4-二羟基苯基或4-羟基-3-甲氧基苯基取代基的化合物（抑制率为59.09％）在25 µM处的蘑菇酪氨酸酶抑制作用比曲酸（抑制作用为18.81％）高得多，后者用作阳性对照。特别地，具有2，4-二羟基苯基的两种肉桂酰胺4和9显示出最强的抑制作用。与酪氨酸酶对接模拟显示，这三个cinnamamides，4，9，和10，与曲酸相比，与酪氨酸酶的活性位点的

  DOI：

  10.1016/j.bmc.2018.10.014
• 作为产物：
  描述：

  2,4-二苄氧基苯甲醛 在 potassium carbonate 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 48.0h， 生成 (E)-3-(2,4-bis(benzyloxy)phenyl)acrylic acid
  参考文献：
  名称：

  肉桂酰胺衍生物的合成及其在α-MSH刺激的B16F10黑色素瘤细胞中的抗黑色素作用

  摘要：

  在调节黑色素生物合成的三种酶，酪氨酸酶及其相关蛋白TYRP-1和TYRP-2中，酪氨酸酶是最重要的，因为它能够限制黑色素细胞中黑色素的产生速率。对于治疗由黑色素过量引起的皮肤色素沉着症，酪氨酸酶的抑制是迄今为止最成熟的策略。肉桂酸是一种安全的天然产物，具有（E）-β-苯基-α，β-不饱和羰基，我们先前已证明其在抑制酪氨酸酶中起重要作用。由于肉桂酸相对亲水，这阻碍了它在皮肤上的吸收，因此少了十五种亲水性肉桂酰胺衍生物（1 – 15）被设计为安全且更有效的酪氨酸酶抑制剂，并通过Horner-Wadsworth-Emmons反应合成。使用浓的去苄基化-HCl和乙酸ö苄基-保护的肉桂酰胺40 - 54产生以下三个结果。1）肉桂酰胺类43，48，和53与2,4-组二苄，无论胺类型的酰胺的，产生具有高极性配位化合物。2）肉桂酰胺类40 - 42，44，50 - 52，和54用苄基氨基，或二乙胺基取代产生了所需的脱苄基肉桂酰胺13，5，10

  DOI：

  10.1016/j.ejmech.2018.10.025

文献信息

• [EN] AGONISTS OF GPR40<br/>[FR] AGONISTES DE GPR40
  申请人：CONNEXIOS LIFE SCIENCES PVT LTD

  公开号：WO2012011125A1

  公开（公告）日：2012-01-26

  The present invention relates to compounds that have the ability to modulate the activity of GPR40 and are therefore useful in the treatment of GPR40 related disorders. In addition the invention relates to the compounds, methods for their preparation, pharmaceutical compositions containing the compounds and the uses of these compounds in the treatment of certain disorders related to GPR40 activity.

  本发明涉及具有调节GPR40活性能力的化合物，因此在治疗与GPR40相关的疾病方面具有用处。此外，该发明涉及这些化合物、其制备方法、含有这些化合物的药物组合物以及在治疗与GPR40活性相关的某些疾病方面使用这些化合物的用途。
• Substituted phenyl compounds
  申请人：Rhone-Poulenc Rorer Limited

  公开号：US06211234B1

  公开（公告）日：2001-04-03

  Compounds of formula (I) are described wherein R1 is hydrogen, -(lower alkyl)q(CO2R6 or OH), —CN, —C(R7)═NOR8, NO2, —O(lower alkyl)R9, —C≡C—R10, —CR11═C(R12)(R13), —C(═O)CH2C(═O)CO2H, —CO(R14), alkylthio, alkylsulphinyl, alkylsulphonyl, carbamoyl, thiocarbamoyl, substituted carbamoyl, substituted thiocarbamoyl, sulphamoyl or an optionally substituted nitrogen-containing ring, m, n, o and p are independently zero or 1 and R2, R3, R4 and R5 are various groups; and physiologically acceptable salts, N-oxides and prodrugs thereof. The compounds have endothelin antagonist activity and are useful as pharmaceuticals.

  式(I)的化合物描述如下，其中R1为氢，-(较低烷基)q(CO2R6或OH)，—CN，—C(R7)HNOR8，NO2，—O(较低烷基)R9，—C≡C—R10，—CR11CH(R12)(R13)，—C(O)CH2C(O)CO2H，—CO(R14)，烷基硫醚，烷基亚砜基，烷基磺酰基，氨基甲酰基，硫代氨基甲酰基，取代的氨基甲酰基，取代的硫代氨基甲酰基，磺酰胺基或可选择取代的含氮环，m、n、o和p独立地为零或1，R2、R3、R4和R5为各种基团；以及其生理学上可接受的盐、N-氧化物和前药。这些化合物具有内皮素拮抗活性，并可用作药物。
• AGONISTS OF GPR40
  申请人：Ranganath Rao Jagannath Madanahalli

  公开号：US20130237571A1

  公开（公告）日：2013-09-12

  The present invention relates to compounds that have the ability to modulate the activity of GPR40 and are therefore useful in the treatment of GPR40 related disorders. In addition the invention relates to the compounds, methods for their preparation, pharmaceutical compositions containing the compounds and the uses of these compounds in the treatment of certain disorders related to GPR40 activity.

  本发明涉及具有调节GPR40活性能力的化合物，因此在治疗与GPR40相关的疾病方面非常有用。此外，本发明还涉及这些化合物的制备方法、含有这些化合物的制药组合物以及在治疗与GPR40活性相关的某些疾病方面使用这些化合物的用途。
• Selective endothelin A receptor ligands. 1. Discovery and structure-activity of 2,4-disubstituted benzoic acid derivatives
  作者：PC Astles、TJ Brown、CM Handscombe、MF Harper、NV Harris、RA Lewis、PM Lockey、C McCarthy、IM McLay、B Porter、AG Roach、C Smith、RJA Walsh

  DOI：10.1016/s0223-5234(97)81678-9

  日期：1997.5

  This paper describes the discovery of a new non-peptide endothelin A (ETA) selective ligand, 2,4-dibenzyloxybenzoic acid 3, which inhibits the binding of [I-125]ET-1 to ETA receptors with an IC50 of 9 mu M (ET-1 = endothelin-1). Optimisation of 3 resulted in compound 52 which had an IC50 of 1 mu M. One of the analogues of 3, compound 15, was examined in a functional assay and shown to antagonise ET-1-induced contraction of rat aorta. The identification of 3 was made through the application of ChemDBS-3D searching of our corporate database. The 3D query, using an aromatic ring to a carboxylic acid group separated by 10.2 +/- 1.1 Angstrom, was derived from an examination of common pharmacophoric distances found in the low energy conformations of two known ETA antagonists, the cyclic pentapeptide BQ 123 1 and myriceron caffeoyl ester 2.
• Tyrosinase inhibition and anti-melanin generation effect of cinnamamide analogues
  作者：Sultan Ullah、Chaeun Park、Muhammad Ikram、Dongwan Kang、Sanggwon Lee、Jungho Yang、Yujin Park、Sik Yoon、Pusoon Chun、Hyung Ryong Moon

  DOI：10.1016/j.bioorg.2019.03.001

  日期：2019.6

  Abnormal melanogenesis results in excessive production of melanin, leading to pigmentation disorders. As a key and rate-limiting enzyme for melanogenesis, tyrosinase has been considered an important target for developing therapeutic agents of pigment disorders. Despite having an (E)-beta-phenyl-alpha,beta-unsaturated carbonyl scaffold, which plays an important role in the potent inhibition of tyrosinase activity, cinnamic acids have not attracted attention as potential tyrosinase inhibitors, due to their low tyrosinase inhibitory activity and relatively high hydrophilicity. Given that cinnamic acids' structure intrinsically features this (E)-scaffold and following our experience that minute changes in the chemical structure can powerfully affect tyrosinase activity, twenty less hydrophilic cinnamamide derivatives were designed as potential tyrosinase inhibitors and synthesised using a Horner-Wadsworth-Emmons reaction. Four of these cinnmamides (4, 9, 14, and 19) exhibited much stronger mushroom tyrosinase inhibition (over 90% inhibition) at 25 mu M compared to kojic acid (20.57% inhibition); crucially, all four have a 2,4-dihydroxy group on the beta-phenyl ring of the scaffold. A docking simulation using tyrosinase indicated that the four cinnamamides exceeded the binding affinity of kojic acid, and bound more strongly to the active site of tyrosinase. Based on the strength of their tyrosinase inhibition, these four cinnamamides were further evaluated in B16F10 melanoma cells. All four cinnamamides, without cytotoxicity, exhibited higher tyrosinase inhibitory activity (67.33 - 79.67% inhibition) at 25 mu M than kojic acid (38.11% inhibition), with the following increasing inhibitory order: morpholino (9) = cyclopentylamino (14) < cyclohexylamino (19) < N-methylpiperazino (4) cinnamamides. Analysis of tyrosinase activity and melanin content in B16F10 cells showed that the four cinnamamides dose-dependently inhibited both cellular tyrosinase activity and melanin content and that their inhibitory activity at 25 mu M was much better than that of kojic acid. The results of melanin content analysis well matched those of the cellular tyrosinase activity analysis, indicating that tyrosinase inhibition by the four cinnamamides is a major factor in the reduction of melanin production. These results imply that these four cinnamamides with a 2,4-dihydroxyphenyl group can act as excellent anti-melanogenic agents in the treatment of pigmentation disorders.