2-cyano-N-{2-[2-cyano-3-(3-methoxyphenyl)-acryloylamino]ethyl}-3-(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: 2-cyano-N-{2-[2-cyano-3-(3-methoxyphenyl)-acryloylamino]ethyl}-3-(3-methoxyphenyl)-acrylamide
• 英文别名: 2-cyano-N-{2-[2-cyano-3-(3-methoxyphenyl)acryloylamino]ethyl}-3-(3-methoxyphenyl)acrylamide；(E)-2-cyano-N-[2-[[(E)-2-cyano-3-(3-methoxyphenyl)prop-2-enoyl]amino]ethyl]-3-(3-methoxyphenyl)prop-2-enamide
• 化学式: C₂₄H₂₂N₄O₄
• 分子量: 430.463
• InChiKey: YYXCVYFHTZPKLO-AYKLPDECSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  32
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.17
• 拓扑面积：
  124
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2-氰基-N-[2-[(2-氰基乙酰基)氨基]乙基]乙酰胺 、 3-甲氧基苯甲醛 在 哌啶 作用下， 以 乙醇 为溶剂， 反应 2.0h， 以65%的产率得到2-cyano-N-{2-[2-cyano-3-(3-methoxyphenyl)-acryloylamino]ethyl}-3-(3-methoxyphenyl)-acrylamide
  参考文献：
  名称：

  Parallel Solution-Phase Synthesis of Targeted Tyrphostin Libraries with Anticancer Activity

  摘要：

  半自动化、优雅的合成和并行溶液相合成方法的结合，使我们开发出了五个有针对性的对称酪磷脂化合物库。这些化合物库平均由 12 个化合物组成。尽管如此，我们还是发现了针对 HT29（结直肠癌）和 G401（肾癌）细胞系的低微摩尔强效生长抑制剂。此外，我们还获得了重要的 SAR 数据。我们注意到，具有 2-氯苯基的类似物始终具有最强的生长抑制活性（10：GI50 HT29 5.5 ± 0.4 μM，GI50 G401 2.6 ± 0.4 μM；23：GI50 HT29 2.4 ± 0.2 μM，GI50 G401 1.9 ± 1 μM；34：GI50 HT29 8.8 ± 0.2 μM，GI50 G401 1.9 ± 1 μM）：对于 34：GI50 HT29 8.8 ± 3.1 μM，GI50 G401 6.2 ± 2.9 μM；对于 46：GI50 HT29 5.2 ± 0.9 μM，GI50 G401 3.7 ± 0.6 μM；对 57：GI50 HT29 4.6 ± 0.8 μM，GI50 G401 2.1 ± 0.2 μM）、3-氯苯（对 11：GI50 HT29 3.8 ± 0.7 μM，GI50 G401 1.7 ± 0.7 μM；对于 48：GI50 HT29 5.9 ± 0.1 μM，GI50 G401 3.4 ± 0.6 μM；对于 58：GI50 HT29 4.8 ± 0.9 μM，GI50 G401 3.4 ± 0.2 μM），或 3-甲氧基苯基取代基（对于 13：GI50 HT29 7.4 ± 3.8 μM，GI50 G401 2.8 ± 0.5 μM；对于 26：对于 26：GI50 HT29 4.5 ± 0.5 μM，GI50 G401 4.9 ± 1 μM；对于 37：GI50 HT29 3.7 ± 0.2 μM，GI50 G401 1.6 ± 0.2 μM；49：GI50 HT29 3.7 ± 0.4 μM，GI50 G401 3.4 ± 0.2 μM；60：GI50 HT29 4.1 ± 0.6 μM，GI50 G401 1.8 ± 0.3 μM）。最后，我们注意到，增加末端芳香环之间的距离对 2-、3-氯苯基和 3-甲氧基苯基类似物的影响很小，但对 OH、COOH 和多重取代的类似物有有利影响。

  DOI：

  10.1071/ch04143

文献信息

• Small Molecule Inhibitors of Dynamin I GTPase Activity:  Development of Dimeric Tyrphostins
  作者：Timothy Hill、Luke R. Odell、Jennifer K. Edwards、Mark E. Graham、Andrew B. McGeachie、Jenny Rusak、Annie Quan、Ruben Abagyan、Janet L. Scott、Phillip J. Robinson、Adam McCluskey

  DOI：10.1021/jm040208l

  日期：2005.12.1

  Dynamin I is a GTPase enzyme required for endocytosis and is an excellent target for the design of potential endocytosis inhibitors. Screening of a library of tyrphostins, in our laboratory, against the GTPase activity of dynamin I gave rise to a mu M potent lead, 2-cyano-3-(3,4-dihydroxyphenyl)thioacrylamide (1, IC50 70 mu M). Our initial investigations suggested that only the dimeric form of 1 displayed dynamin I GTPase inhibitory activity. Subsequent synthetic iterations were based on dimeric analogues and afforded a number of small molecules, low mu M potent, inhibitors of dynamin I GTPase, in particular, symmetrical analogues with a minimum of two free phenolic -OHs: catechol-acrylamide (9) (IC50 = 5.1 +/- 0.6 mu M), its 3,4,5-trihydroxy congener (10) (IC50 = 1.7 +/- 0.2 mu M), and the corresponding 3-methyl ether (11) (IC50 = 9 3 mu M). Increasing the length of the central alkyl spacer from ethyl to propyl (22-24) afforded essentially identical activity with IC50'S of 1.7 0.2, 1.7 0.2, and 5 +/- 1 mu M, respectively. No decrease in activity was noted until the introduction of a hexyl spacer. Our studies highlight the requirement for two free amido NHs with neither the mono-N-methyl (86) nor the bis-N-methyl (87) analogues inhibiting dynamin I GTPase. A similar effect was noted for the removal of the nitrile moieties. However, modest potency was observed with the corresponding ester analogues of 9-11: ethyl ester (90), propyl ester (91), and butyl ester (92), with IC50'S of 42 3, 38 2, and 61 2 mu M, respectively. Our studies reveal the most potent and promising dynamin I GTPase inhibitor in this series as (22), which is also known as BisT.