AG 548 | 168835-84-5

• 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: AG 548
• 英文别名: (E,E)-2-›[2-[[1-cyano-2(3,4-dihydroxyphenyl)ethenyl]carbonylamino]ethyl] aminocarbonyl-3-(3,4-dihydroxyphenyl)acrylonitrile；(E,E)-2-›[2-[[1-cyano-2(3,4-dihydroxyphenyl)ethenyl]carbonylamino]ethyl]aminocarbonyl-3-(3,4-dihydroxyphenyl)acrylonitrile；2-cyano-N-{3-[2-cyano-3-(3,4-dihydroxyphenyl)acryloylamino]-ethyl}-3-(3,4-dihydroxyphenyl)-acrylamide；Dimeric Tyrphostin 3；(E)-2-cyano-N-[2-[[(E)-2-cyano-3-(3,4-dihydroxyphenyl)prop-2-enoyl]amino]ethyl]-3-(3,4-dihydroxyphenyl)prop-2-enamide
• CAS: 168835-84-5
• 化学式: C₂₂H₁₈N₄O₆
• 分子量: 434.408
• InChiKey: PZIRTMUUDNWDHP-BGPOSVGRSA-N

物化性质

• 沸点：
  902.2±65.0 °C(Predicted)
• 密度：
  1.496±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  32
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.09
• 拓扑面积：
  187
• 氢给体数：
  6
• 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 、 3,4-二羟基苯甲醛 在 哌啶 作用下， 以 乙醇 为溶剂， 反应 2.0h， 以81%的产率得到AG 548
  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

• [EN] METHODS AND AGENTS FOR INHIBITING DYNAMIN-DEPENDENT ENDOCYTOSIS<br/>[FR] PROCEDES ET AGENTS POUR INHIBER L'ENDOCYTOSE DEPENDANT DE LA DYNAMINE
  申请人：UNIV NEWCASTLE RES ASS

  公开号：WO2005049009A1

  公开（公告）日：2005-06-02

  There are disclosed methods for inhibiting dynamin-dependent endocytosis in cells comprising treating the cells with an effective amount of a compound of formula (I), or a dimeric tyrphostin, physiologically acceptable salt, or prodrug thereof. Compounds useful in the methods described are also provided. The inhibition of dynamin-dependent endocytosis of cells is applicable to the treatment of epilepsy and neurological disorders and conditions.

  抑制细胞中依赖动力蛋白的内吞作用的方法已被披露，包括将细胞用式(I)的化合物、二聚酪酪激酶抑制剂、生理上可接受的盐或其前药的有效量进行处理。还提供了所述方法中有用的化合物。抑制细胞中依赖动力蛋白的内吞作用适用于治疗癫痫和神经系统疾病和症状。
• 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。
• Compounds for the treatment of disorders related to vasculogenesis
  申请人：Yissum Research Development Corp.

  公开号：US05712395A1

  公开（公告）日：1998-01-27

  The present invention relates to organic molecules capable of modulating tyrosine kinase signal transduction and particularly KDR/FLK-1 receptor signal transduction in order to regulate and/or modulate vasculogenesis and angiogenesis. The invention is based, in part, on the demonstration that KDR/FLK-1 tyrosine kinase receptor expression is associated with endothelial cells and the identification of vascular endothelial growth factor (VEGF) as the high affinity ligand of FLK-1. These results indicate a major role for KDR/FLK-1 in the signaling system during vasculogenesis and angiogenesis. Engineering of host cells that express FLK-1 and the uses of expressed FLK-1 to evaluate and screen for drugs and analogs of VEGF involved in FLK-1 modulation by either agonist or antagonist activities is also described. The invention also relates to the use of the disclosed compounds in the treatment of disorders, including cancer, diabetes, hemangioma and Kaposi's sarcoma, which are related to vasculogenesis and angiogenesis.

  本发明涉及有机分子，能够调节酪氨酸激酶信号传导，特别是KDR/FLK-1受体信号传导，以调节和/或调控血管生成和血管新生。该发明部分基于KDR/FLK-1酪氨酸激酶受体表达与内皮细胞相关，并鉴定血管内皮生长因子（VEGF）为FLK-1的高亲和配体。这些结果表明KDR/FLK-1在血管生成和血管新生期间的信号系统中起着重要作用。还描述了表达FLK-1的宿主细胞的工程以及利用表达的FLK-1评估和筛选通过激动剂或拮抗剂活性调节FLK-1的VEGF药物和类似物。该发明还涉及使用所披露的化合物治疗与血管生成和血管新生相关的疾病，包括癌症、糖尿病、血管瘤和Kaposi肉瘤。
• Quinazoline compounds and compositions thereof for the treatment of
  申请人：Sugen, Inc.

  公开号：US05792771A1

  公开（公告）日：1998-08-11

  The present invention relates to organic molecules capable of modulating tyrosine kinase signal transduction and particularly KDR/FLK-1 receptor signal transduction in order to regulate and/or modulate vasculogenesis and angiogenesis. The invention is based, in part, on the demonstration that KDR/FLK-1 tyrosine kinase receptor expression is associated with endothelial cells and the identification of vascular endothelial growth factor (VEGF) as the high affinity ligand of FLK-1. These results indicate a major role for KDR/FLK-1 in the signaling system during vasculogenesis and angiogenesis. Engineering of host cells that express FLK-1 and the uses of expressed FLK-1 to evaluate and screen for drugs and analogs of VEGF involved in FLK-1 modulation by either agonist or antagonist activities is also described. The invention also relates to the use of the disclosed compounds in the treatment of disorders, including cancer, diabetes, hemangioma and Kaposi's sarcoma, which are related to vasculogenesis and angiogenesis.

  本发明涉及有机分子，能够调节酪氨酸激酶信号传导，特别是KDR/FLK-1受体信号传导，以调节和/或调节血管生成和血管新生。该发明部分基于KDR/FLK-1酪氨酸激酶受体表达与内皮细胞相关，并确定血管内皮生长因子（VEGF）为FLK-1的高亲和力配体的论证。这些结果表明KDR/FLK-1在血管生成和血管新生过程中的信号系统中起着重要作用。描述了表达FLK-1的宿主细胞的工程化，以及利用表达的FLK-1评估和筛选参与FLK-1调节的VEGF的药物和类似物，无论是通过激动剂还是拮抗剂活性。该发明还涉及使用所披露的化合物治疗与血管生成和血管新生相关的疾病，包括癌症、糖尿病、血管瘤和卡波西肉瘤。
• Tyrphostins. 6. Dimeric Benzylidenemalononitrile Tyrphostins:  Potent Inhibitors of EGF Receptor Tyrosine Kinase <i>in Vitro</i>
  作者：Aviv Gazit、Nir Osherov、Chaim Gilon、Alexander Levitzki

  DOI：10.1021/jm960225d

  日期：1996.1.1

  Benzylidenemalononitrile (BMN) tyrphostins were previously found to be potent inhibitors of EGF receptor (EGFR) tyrosine kinase activity. Since these compounds were found to compete for the substrate and sometimes with the ATP site and since EGFR acts as a dimer, we prepared a series of dimeric tyrphostins. These dimeric tyrphostins were built from two BMN units linked by various spacers and designed to fit the dimeric cross-autophosphorylation signal transduction intermediate of the EGFR tyrosine kinases. Structure-activity relationship of these potent dimeric EGF receptor tyrosine kinase inhibitors is reported.