(E)-N-cyclohexyl-3-(4-hydroxy-3-methoxyphenyl)acrylamide

• 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)-N-cyclohexyl-3-(4-hydroxy-3-methoxyphenyl)acrylamide
• 英文别名: (E)-N-cyclohexyl-3-(4-hydroxy-3-methoxyphenyl)prop-2-enamide
• 化学式: C₁₆H₂₁NO₃
• 分子量: 275.348
• InChiKey: PGUHGTBZHNKXDM-CSKARUKUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  20
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  58.6
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  (E)-3-(4-(苄氧基)-3-甲氧基苯基)丙烯酸乙酯 在 N-甲基吗啉 、 盐酸 、 溶剂黄146 、 sodium hydroxide 、 氯甲酸异丁酯 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 水 为溶剂， 反应 73.17h， 生成 (E)-N-cyclohexyl-3-(4-hydroxy-3-methoxyphenyl)acrylamide
  参考文献：
  名称：

  Tyrosinase inhibition and anti-melanin generation effect of cinnamamide analogues

  摘要：

  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.

  DOI：

  10.1016/j.bioorg.2019.03.001

文献信息

• Ferulic acid amide derivatives as anticancer and antioxidant agents: synthesis, thermal, biological and computational studies
  作者：Naresh Kumar、Sandeep Kumar、Sheenu Abbat、Kumar Nikhil、Sham M. Sondhi、Prasad V. Bharatam、Partha Roy、Vikas Pruthi

  DOI：10.1007/s00044-016-1562-6

  日期：2016.6

  respect to their parent molecule. Previous reports for the biological applications of ferulic acid amides also confirmed the importance of work presented here. The 3D-QSAR studies for anticancer and antioxidant activities were also performed by using CoMFA, and the corresponding contour maps of electrostatic and steric fields have been computed. Statistical analysis between experimental and CoMFA-predicted

  摘要在无溶剂条件下完成了阿魏酸单酰胺和双酰胺衍生物的四个系列（IIIa–IIIo，Va–Vg，VIIa–VIIg和IXa–IXe）的设计和微波辅助合成，其特征在于光谱技术。在热分析过程中，发现所有化合物在高达100°C的温度下均稳定，并在较高的温度下通过一步分解。分别对衍生物的体外细胞毒性和抗氧化活性进行了筛选，观察到化合物Vb对乳房的活性最高（MCF-7； IC 50  = 07.49 µM和MDA-MB-231； IC 50  = 07.28 µM），Vd对乳房最有效。肺（A549； IC 50 = 07.11μM）和肝（HepG2细胞; IC 50  = 08.32μM）和Ve的免受子（HeLa细胞; IC 50  = 07.14μM）癌细胞系，而化合物IIIF，IIIL，IIIO，VIIE和IXA-IXE发现显示相对于其母体分子具有很强的抗氧化活性。先前关于阿魏酰胺的生物学应用的报
• Development of Semisynthetic Apoptosis-Inducing Agents Based on Natural Phenolic Acids Scaffold: Design, Synthesis and In-Vitro Biological Evaluation
  作者：Shahira M. Ezzat、Heba El Sayed Teba、Inas G. Shahin、Ahmed M. Hafez、Aliaa M. Kamal、Nora M. Aborehab

  DOI：10.3390/molecules27196724

  日期：——

  A crucial target in drug research is magnifying efficacy and decreasing toxicity. Therefore, using natural active constituents as precursors will enhance both safety and biological activities. Despite having many pharmacological activities, caffeic and ferulic acids showed limited clinical usage due to their poor bioavailability and fast elimination. Therefore, semisynthetic compounds from these two acids were prepared and screened as anticancer agents. In this study, CA and FA showed very potent anticancer activity against Caco-2 cells. Consequently, eighteen derivatives were tested against the same cell line. Four potent candidates were selected for determination of the selectivity index, where compound 10 revealed a high safety margin. Compound 10 represented a new scaffold and showed significant cytotoxic activity against Caco-2. Cell-cycle analysis and evaluation of apoptosis showed that derivatives 10, 7, 11, 15 and 14 showed the highest proportion of cells in a late apoptotic stage.

  药物研究的一个重要目标是提高疗效和降低毒性。因此，使用天然活性成分作为前体将提高安全性和生物活性。尽管咖啡酸和阿魏酸具有多种药理活性，但由于它们的生物利用度低、消除速度快，因此临床应用有限。因此，我们制备了这两种酸的半合成化合物，并将其作为抗癌剂进行筛选。在这项研究中，CA 和 FA 对 Caco-2 细胞显示出非常强的抗癌活性。因此，研究人员针对同一细胞系测试了 18 种衍生物。在确定选择性指数时，选出了四种有效的候选化合物，其中化合物 10 显示出较高的安全系数。化合物 10 代表了一种新的支架，对 Caco-2 细胞具有显著的细胞毒性活性。细胞周期分析和细胞凋亡评估显示，衍生物 10、7、11、15 和 14 中细胞凋亡晚期的比例最高。
• NOVEL COMPOUNDS AND USE THEREOF AS MEDICINE
  申请人：TSUMURA & CO.

  公开号：EP0535250A1

  公开（公告）日：1993-04-07

  Specified cinnamic acid derivatives, such as methyl 4-(4-acetoxy-3-methoxycinnamamide)-1-methyl-1-cyclohexanecarboxylate, and pharmaceutically acceptable salts thereof, which are useful as an allergy type IV reaction inhibitor.

  特定肉桂酸衍生物，如 4-(4-乙酰氧基-3-甲氧基肉桂酰胺)-1-甲基-1-环己烷羧酸甲酯及其药学上可接受的盐，可用作 IV 型过敏反应抑制剂。
• New cannamide derivatives and their use as allergy inhibitors
  申请人：TSUMURA & CO.

  公开号：EP0705817A1

  公开（公告）日：1996-04-10

  New cinnamic acid derivatives, such as methyl 4-(4-acetoxy-3-methoxycinnamanide)-1-cyclohexanecarboxylate, and pharmaceutically acceptable salts thereof, are useful as IV-type allergic reaction-suppressive drugs.

  新型肉桂酸衍生物，如 4-(4-乙酰氧基-3-甲氧基肉桂酸)-1-环己烷羧酸甲酯及其药学上可接受的盐类，可用作 IV 型过敏反应抑制药物。
• US5344845A
  申请人：——

  公开号：US5344845A

  公开（公告）日：1994-09-06