3-amino-6-[2-(dimethylamino)ethylamino]-N-[(3-methylimidazol-4-yl)methylideneamino]-4-phenylthieno[2,3-b]pyridine-2-carboxamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 3-amino-6-[2-(dimethylamino)ethylamino]-N-[(3-methylimidazol-4-yl)methylideneamino]-4-phenylthieno[2,3-b]pyridine-2-carboxamide
• 化学式: C₂₂H₂₅BrN₃O₅Pol
• InChiKey: ZHJGRATWVYGUMB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  None
• 重原子数：
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• 可旋转键数：
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• 环数：
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• sp3杂化的碳原子比例：
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• 拓扑面积：
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• 氢给体数：
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• 氢受体数：
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反应信息

• 作为反应物：
  描述：

  炔丙胺 、 3-amino-6-[2-(dimethylamino)ethylamino]-N-[(3-methylimidazol-4-yl)methylideneamino]-4-phenylthieno[2,3-b]pyridine-2-carboxamide 以 二甲基亚砜 为溶剂， 反应 4.0h， 生成 3'-[[(1,1-dimethylethoxy)carbonyl]amino]-[1,1'-biphenyl]-4-carbonyl-L-phenylalanine methyl ester
  参考文献：
  名称：

  Small molecule antagonists of the urokinase (uPA): urokinase receptor (uPAR) interaction with high reported potencies show only weak effects in cell-based competition assays employing the native uPAR ligand

  摘要：

  Binding of the urokinase-type plasminogen activator (uPA) to its cell-surface-bound receptor uPAR and upregulation of the plasminogen activation system (PAS) correlates with increased metastasis and poor prognosis in several tumour types. Disruptors of the uPA: uPAR interaction represent promising antitumour/metastasis agents and several approaches have been explored for this purpose, including the use of small molecule antagonists. Two highly potent non-peptidic antagonists 1 and 2 (IC50 1 = 0.8 nM, IC50 2 = 33 nM) from the patent literature were reportedly identified using competition assays employing radiolabelled uPAR-binding uPA fragments and appeared as useful pharmacological tools for studying the PAS. Before proceeding to such studies, confirmation was sought that 1 and 2 retained their potencies in physiologically relevant cell-based competition assays employing uPAR's native binding partner high molecular weight uPA (HMW-uPA). This study describes a new solution phase synthesis of 1, a mixed solid/solution phase synthesis of 2 and reports the activities of 1 and 2 in semi-quantitative competition flow cytometry assays and quantitative cell-based uPA activity assays that employed HMW-uPA as the competing ligand. The flow cytometry experiments revealed that high concentrations of 2 (10-100 mu M) are required to compete with HMW-uPA for uPAR binding and that 1 shows no antagonist effects at 100 mu M. The cell-based enzyme activity assays similarly revealed that 1 and 2 are poor inhibitors of cell surface-bound HMW-uPA activity (IC50 > 100 mu M for 1 and 2). The report highlights the dangers of identifying false-positive lead uPAR antagonists from competition assays employing labelled competing ligands other than the native HMW-uPA. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.03.016

文献信息

• Small molecule antagonists of the urokinase (uPA): urokinase receptor (uPAR) interaction with high reported potencies show only weak effects in cell-based competition assays employing the native uPAR ligand
  作者：Melissa De Souza、Hayden Matthews、Jodi A. Lee、Marie Ranson、Michael J. Kelso

  DOI：10.1016/j.bmc.2011.03.016

  日期：2011.4

  Binding of the urokinase-type plasminogen activator (uPA) to its cell-surface-bound receptor uPAR and upregulation of the plasminogen activation system (PAS) correlates with increased metastasis and poor prognosis in several tumour types. Disruptors of the uPA: uPAR interaction represent promising antitumour/metastasis agents and several approaches have been explored for this purpose, including the use of small molecule antagonists. Two highly potent non-peptidic antagonists 1 and 2 (IC50 1 = 0.8 nM, IC50 2 = 33 nM) from the patent literature were reportedly identified using competition assays employing radiolabelled uPAR-binding uPA fragments and appeared as useful pharmacological tools for studying the PAS. Before proceeding to such studies, confirmation was sought that 1 and 2 retained their potencies in physiologically relevant cell-based competition assays employing uPAR's native binding partner high molecular weight uPA (HMW-uPA). This study describes a new solution phase synthesis of 1, a mixed solid/solution phase synthesis of 2 and reports the activities of 1 and 2 in semi-quantitative competition flow cytometry assays and quantitative cell-based uPA activity assays that employed HMW-uPA as the competing ligand. The flow cytometry experiments revealed that high concentrations of 2 (10-100 mu M) are required to compete with HMW-uPA for uPAR binding and that 1 shows no antagonist effects at 100 mu M. The cell-based enzyme activity assays similarly revealed that 1 and 2 are poor inhibitors of cell surface-bound HMW-uPA activity (IC50 > 100 mu M for 1 and 2). The report highlights the dangers of identifying false-positive lead uPAR antagonists from competition assays employing labelled competing ligands other than the native HMW-uPA. (C) 2011 Elsevier Ltd. All rights reserved.