2-[N-[2-amino-2-oxoethyl]-2-[N-(naphthalen-2-yl)-2-(prop-2-ynylamino)acetamido]acetamido]acetic acid trifluoroacetate | 1309100-68-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: 2-[N-[2-amino-2-oxoethyl]-2-[N-(naphthalen-2-yl)-2-(prop-2-ynylamino)acetamido]acetamido]acetic acid trifluoroacetate
• CAS: 1309100-68-2
• 化学式: C₂HF₃O₂*C₂₁H₂₂N₄O₅
• 分子量: 524.453
• InChiKey: VHOUTPQQSDXJLK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.43
• 重原子数：
  37.0
• 可旋转键数：
  10.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  170.34
• 氢给体数：
  4.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  2-[N-[2-amino-2-oxoethyl]-2-[N-(naphthalen-2-yl)-2-(prop-2-ynylamino)acetamido]acetamido]acetic acid trifluoroacetate 、 4,4'-二甲氧基二苯甲胺 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 、 盐酸 作用下， 以 N,N-二甲基甲酰胺 、 水 、 二甲基亚砜 、 乙腈 为溶剂， 反应 24.0h， 以28%的产率得到N-[2-amino-2-oxoethyl]-N-[2-[bis(4-methoxyphenyl)methylamino]-2-oxoethyl]-2-[N-[naphthalen-2-yl]-2-[prop-2-ynylamino]acetamido]acetamide hydrochloride
  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
• 作为产物：
  描述：

  三氟乙酸 、 3'-[[(1,1-dimethylethoxy)carbonyl]amino]-[1,1'-biphenyl]-4-carbonyl-L-phenylalanine methyl ester 在 三异丙基硅烷 作用下， 以 水 为溶剂， 反应 1.0h， 以112 mg的产率得到2-[N-[2-amino-2-oxoethyl]-2-[N-(naphthalen-2-yl)-2-(prop-2-ynylamino)acetamido]acetamido]acetic acid trifluoroacetate
  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