2-cyano-N-{2-[2-cyano-3-(4-carboxyphenyl)-acryloylamino]ethyl}-3-(4-carboxyphenyl)-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-(4-carboxyphenyl)-acryloylamino]ethyl}-3-(4-carboxyphenyl)-acrylamide
• 英文别名: 2-cyano-N-{2-[2-cyano-3-(4-carboxyphenyl)acryloylamino]ethyl}-3-(4-carboxyphenyl)acrylamide；4-[(E)-3-[2-[[(E)-3-(4-carboxyphenyl)-2-cyanoprop-2-enoyl]amino]ethylamino]-2-cyano-3-oxoprop-1-enyl]benzoic acid
• 化学式: C₂₄H₁₈N₄O₆
• 分子量: 458.43
• InChiKey: BVIVMMGASMKPFW-AYKLPDECSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  34
• 可旋转键数：
  9
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  180
• 氢给体数：
  4
• 氢受体数：
  8

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 、 对醛基苯甲酸 在 哌啶 作用下， 以 乙醇 为溶剂， 反应 2.0h， 以96%的产率得到2-cyano-N-{2-[2-cyano-3-(4-carboxyphenyl)-acryloylamino]ethyl}-3-(4-carboxyphenyl)-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

• Parallel Solution-Phase Synthesis of Targeted Tyrphostin Libraries with Anticancer Activity
  作者：Timothy A. Hill、Jennette A. Sakoff、Phillip J. Robinson、Adam McCluskey

  DOI：10.1071/ch04143

  日期：——

  The combination of semi-automation, an elegant synthesis, and parallel solution-phase synthesis approaches has allowed the development of five targeted, symmetrical tyrphostin compound libraries. These libraries on average are comprised of 12 compounds. Notwithstanding this, low micromolar potent growth inhibitors against HT29 (colorectal carcinoma) and G401 (renal carcinoma) cell lines were discovered. Additionally, significant SAR data was obtained. We noted that the most potent growth inhibitory activity was consistently observed for those analogues that possessed a 2-chlorophenyl (for 10: GI50 HT29 5.5 ± 0.4 μM, GI50 G401 2.6 ± 0.4 μM; for 23: GI50 HT29 2.4 ± 0.2 μM, GI50 G401 1.9 ± 1 μM; for 34: GI50 HT29 8.8 ± 3.1 μM, GI50 G401 6.2 ± 2.9 μM; for 46: GI50 HT29 5.2 ± 0.9 μM, GI50 G401 3.7 ± 0.6 μM; for 57: GI50 HT29 4.6 ± 0.8 μM, GI50 G401 2.1 ± 0.2 μM), a 3-chlorophenyl (for 11: GI50 HT29 3.8 ± 0.7 μM, GI50 G401 1.7 ± 0.7 μM; for 48: GI50 HT29 5.9 ± 0.1 μM, GI50 G401 3.4 ± 0.6 μM; for 58: GI50 HT29 4.8 ± 0.9 μM, GI50 G401 3.4 ± 0.2 μM), or a 3-methoxyphenyl substituent (for 13: GI50 HT29 7.4 ± 3.8 μM, GI50 G401 2.8 ± 0.5 μM; for 26: GI50 HT29 4.5 ± 0.5 μM, GI50 G401 4.9 ± 1 μM; for 37: GI50 HT29 3.7 ± 0.2 μM, GI50 G401 1.6 ± 0.2 μM; for 49: GI50 HT29 3.7 ± 0.4 μM, GI50 G401 3.4 ± 0.2 μM; for 60: GI50 HT29 4.1 ± 0.6 μM, GI50 G401 1.8 ± 0.3 μM). Finally, we noted that increasing the distance between the terminal aromatic rings had only a minimal effect on the 2-, 3-chlorophenyl, and 3-methoxyphenyl analogues, but did have a favourable effect on OH, COOH, and multiply substituted analogues.

  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。
• 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.