benzyl 2-(benzyloxy)-4-(N-(4-cyclohexylbenzyl)-2-(2,3,4,5,6-pentafluoro-N-methylphenylsulfonamido)acetamido)benzoate | 1334493-48-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: benzyl 2-(benzyloxy)-4-(N-(4-cyclohexylbenzyl)-2-(2,3,4,5,6-pentafluoro-N-methylphenylsulfonamido)acetamido)benzoate
• 英文别名: benzyl 4-[(4-cyclohexylphenyl)methyl-[2-[methyl-(2,3,4,5,6-pentafluorophenyl)sulfonylamino]acetyl]amino]-2-phenylmethoxybenzoate
• CAS: 1334493-48-9
• 化学式: C₄₃H₃₉F₅N₂O₆S
• 分子量: 806.85
• InChiKey: HXKUUAMCRHQGLI-UHFFFAOYSA-N

物化性质

• 沸点：
  863.8±75.0 °C(Predicted)
• 密度：
  1.350±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  9.5
• 重原子数：
  57
• 可旋转键数：
  15
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  102
• 氢给体数：
  0
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  benzyl 2-(benzyloxy)-4-(N-(4-cyclohexylbenzyl)-2-(2,3,4,5,6-pentafluoro-N-methylphenylsulfonamido)acetamido)benzoate 在 palladium 10% on activated carbon 、 氢气 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 3.08h， 以77%的产率得到4-[[(4-环己基苯基)甲基][2-[甲基[(2,3,4,5,6-五氟苯基)磺酰基]氨基]乙酰基]氨基]-2-羟基苯甲酸
  参考文献：
  名称：

  Potent Targeting of the STAT3 Protein in Brain Cancer Stem Cells: A Promising Route for Treating Glioblastoma

  摘要：

  The STAT3 gene is abnormally active in glioblastoma (GBM) and is a critically important mediator of tumor growth and therapeutic resistance in GBM. Thus, for poorly treated brain cancers such as gliomas, astrocytomas, and glioblastomas, which harbor constitutively activated STAT3, a STAT3-targeting therapeutic will be of significant importance. Herein, we report a most potent, small molecule, nonphosphorylated STAT3 inhibitor, 31 (SH-4-54) that strongly binds to STAT3 protein (K-D = 300 nM). Inhibitor 31 potently kills glioblastoma brain cancer stem cells (BTSCs) and effectively suppresses STAT3 phosphorylation and its downstream transcriptional targets at low nM concentrations. Moreover, in vivo, 31 exhibited blood brain barrier permeability, potently controlled glioma tumor growth, and inhibited pSTAT3 in vivo. This work, for the first time, demonstrates the power of STAT3 inhibitors for the treatment of BTSCs and validates the therapeutic efficacy of a STAT3 inhibitor for GBM clinical application.

  DOI：

  10.1021/ml4003138
• 作为产物：
  描述：

  4-氨基水杨酸 在 potassium tert-butylate 、 sodium cyanoborohydride 、 溶剂黄146 、 三苯基二氯化膦 作用下， 以 甲醇 、 氯仿 、 N,N-二甲基甲酰胺 为溶剂， 反应 7.58h， 生成 benzyl 2-(benzyloxy)-4-(N-(4-cyclohexylbenzyl)-2-(2,3,4,5,6-pentafluoro-N-methylphenylsulfonamido)acetamido)benzoate
  参考文献：
  名称：

  Potent Targeting of the STAT3 Protein in Brain Cancer Stem Cells: A Promising Route for Treating Glioblastoma

  摘要：

  The STAT3 gene is abnormally active in glioblastoma (GBM) and is a critically important mediator of tumor growth and therapeutic resistance in GBM. Thus, for poorly treated brain cancers such as gliomas, astrocytomas, and glioblastomas, which harbor constitutively activated STAT3, a STAT3-targeting therapeutic will be of significant importance. Herein, we report a most potent, small molecule, nonphosphorylated STAT3 inhibitor, 31 (SH-4-54) that strongly binds to STAT3 protein (K-D = 300 nM). Inhibitor 31 potently kills glioblastoma brain cancer stem cells (BTSCs) and effectively suppresses STAT3 phosphorylation and its downstream transcriptional targets at low nM concentrations. Moreover, in vivo, 31 exhibited blood brain barrier permeability, potently controlled glioma tumor growth, and inhibited pSTAT3 in vivo. This work, for the first time, demonstrates the power of STAT3 inhibitors for the treatment of BTSCs and validates the therapeutic efficacy of a STAT3 inhibitor for GBM clinical application.

  DOI：

  10.1021/ml4003138

文献信息

• Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
  申请人：University of Central Florida Research Foundation, Inc.

  公开号：US10196373B2

  公开（公告）日：2019-02-05

  In one aspect, the invention relates to substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs, derivatives thereof, and related compounds, which are useful as inhibitors of STAT protein activity; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders of uncontrolled cellular proliferation associated with a STAT protein activity dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  在一个方面，该发明涉及替代的2-羟基-4-(2-(苯磺酰胺基)乙酰胺基)苯甲酸类似物，其衍生物和相关化合物，这些化合物可用作STAT蛋白活性的抑制剂；制备这些化合物的合成方法；包含这些化合物的药物组合物；以及使用这些化合物和组合物治疗与STAT蛋白活性功能障碍相关的细胞不受控制增殖疾病的方法。本摘要旨在作为在特定领域进行搜索的扫描工具，并不打算限制本发明。
• SUBSTITUTED 2-HYDROXY-4-(2-(PHENYLSULFONAMIDO)ACETAMIDO)BENZOIC ACID ANALOGS AS INHIBITORS OF STAT PROTEIN
  申请人：University of Central Florida Research Foundation, Inc.

  公开号：US20150038708A1

  公开（公告）日：2015-02-05

  In one aspect, the invention relates to substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs, derivatives thereof, and related compounds, which are useful as inhibitors of STAT protein activity; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders of uncontrolled cellular proliferation associated with a STAT protein activity dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

  本发明涉及替代的2-羟基-4-(2-(苯磺酰胺)乙酰胺)苯甲酸类似物、其衍生物和相关化合物，它们可以作为STAT蛋白活性的抑制剂；制备这些化合物的合成方法；包含这些化合物的制药组合物；以及使用这些化合物和组合物治疗与STAT蛋白活性功能障碍相关的细胞增殖失控症状的方法。本摘要旨在作为特定领域搜索的扫描工具，不意味着对本发明的限制。
• SALICYCLIC ACID DERIVATIVES, PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, COMPOSITION THEREOF AND METHOD OF USE THEREOF
  申请人：The Governing Council of the University of Toronto

  公开号：US20150158894A1

  公开（公告）日：2015-06-11

  The present invention relates to novel compounds, compositions containing same and methods for inhibiting STAT3 and/or STAT5 activity or for the treatment of a STAT3 or STAT5-dependent cancer using said compounds; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

  本发明涉及新型化合物、含有该化合物的组合物以及使用该化合物抑制STAT3和/或STAT5活性或治疗STAT3或STAT5依赖性癌症的方法；或其药学上可接受的盐、溶剂或前药。
• Salicylic acid derivatives, pharmaceutically acceptable salt thereof, composition thereof and method of use thereof
  申请人：The Governing Council of the University of Toronto

  公开号：US10377780B2

  公开（公告）日：2019-08-13

  The present invention relates to novel compounds, compositions containing same and methods for inhibiting STAT3 and/or STAT5 activity or for the treatment of a STAT3 or STAT5-dependent cancer using said compounds; or a pharmaceutically acceptable salt, solvate or prodrug thereof.

  本发明涉及抑制 STAT3 和/或 STAT5 活性或使用上述化合物治疗 STAT3 或 STAT5 依赖性癌症的新型化合物、含有上述化合物的组合物和方法； 或其药学上可接受的盐、溶液或原药。
• Identification of a non-phosphorylated, cell permeable, small molecule ligand for the Stat3 SH2 domain
  作者：Brent D.G. Page、Steven Fletcher、Peibin Yue、Zhihua Li、Xiaolei Zhang、Sumaiya Sharmeen、Alessandro Datti、Jeffrey L. Wrana、Suzanne Trudel、Aaron D. Schimmer、James Turkson、Patrick T. Gunning

  DOI：10.1016/j.bmcl.2011.06.056

  日期：2011.9

  Signal transducer and activator of transcription 3 (Stat3) protein is a cytosolic transcription factor that is aberrantly activated in numerous human cancers. Inhibitors of activated Stat3-Stat3 protein complexes have been shown to hold therapeutic promise for the treatment of human cancers harboring activated Stat3. Herein, we report the design and synthesis of a focused library of salicylic acid containing Stat3 SH2 domain binders. The most potent inhibitor, 17o, effectively disrupted Stat3-phosphopeptide complexes (K(i) = 13 mu M), inhibited Stat3-Stat3 protein interactions (IC(50) = 19 mu M) and silenced intracellular Stat3 phosphorylation and Stat3-target gene expression profiles. Inhibition of Stat3 function in both breast and multiple myeloma (MM) tumor cells correlated with induced cell death (EC(50) = 10 and 16 mu M, respectively). (C) 2011 Elsevier Ltd. All rights reserved.