(E)-2-(1-(biphenyl-4-ylmethylene)-5-fluoro-1H-inden-3-yl)ethanoic acid | 1049800-47-6

• 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: (E)-2-(1-(biphenyl-4-ylmethylene)-5-fluoro-1H-inden-3-yl)ethanoic acid
• 英文别名: (E)-2-(1-([1,1'-biphenyl]-4-ylmethylene)-5-fluoro-1H-inden-3-yl)acetic acid；2-[(3E)-6-fluoro-3-[(4-phenylphenyl)methylidene]inden-1-yl]acetic acid
• CAS: 1049800-47-6
• 化学式: C₂₄H₁₇FO₂
• 分子量: 356.396
• InChiKey: VJDZAFANKNWYHT-XDHOZWIPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  27
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.04
• 拓扑面积：
  37.3
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (E)-2-(1-(biphenyl-4-ylmethylene)-5-fluoro-1H-inden-3-yl)ethanoic acid 在 草酰氯 作用下， 以 二氯甲烷 为溶剂， 生成 (E)-2-(1-([1,1'-biphenyl]-4-ylmethylene)-5-fluoro-1H-inden-3-yl)-N-((trifluoromethyl)sulfonyl)acetamide
  参考文献：
  名称：

  Cyclooxygenase-1-Selective Inhibitors Based on the (E)-2′-Des-methyl-sulindac Sulfide Scaffold

  摘要：

  Prostaglandins (PGs) are powerful lipid mediators in many physiological and pathophysiological responses. They are produced by oxidation of arachidonic acid (AA) by cyclo- oxygenases (COX-1 and COX-2) followed by metabolism of endoperoidde intermediates by terminal PG synthases. PG biosynthesis is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). Specific inhibition of COX-2 has been extensively investigated, but relatively few COX-1-selective inhibitors have been described. Recent reports of a possible contribution of COX-1 in analgesia, neuroinflammation, or carcinogenesis suggest that COX-1 is a potential therapeutic target. We designed, synthesized, and evaluated a series of (E)-2'-des-methyl-sulindac sulfide (E-DMSS) analogues for inhibition of COX-1. Several potent and selective inhibitors were discovered, and the most promising compounds were active against COX-1 in intact ovarian carcinoma cells (OVCAR-3). The compounds inhibited tumor cell proliferation but only at concentrations >100-fold higher than the concentrations that inhibit COX-1 activity. E-DMSS analogues may be useful probes of COX-1 biology in vivo and promising leads for COX-1-targeted therapeutic agents.

  DOI：

  10.1021/jm201528b
• 作为产物：
  描述：

  ethyl 2-(6-fluoro-1-hydroxy-1-indanyl)acetate 在 盐酸 、 对甲苯磺酸 、 calcium chloride 作用下， 以 水 、 甲苯 为溶剂， 反应 16.0h， 生成 (E)-2-(1-(biphenyl-4-ylmethylene)-5-fluoro-1H-inden-3-yl)ethanoic acid
  参考文献：
  名称：

  Cyclooxygenase-1-Selective Inhibitors Based on the (E)-2′-Des-methyl-sulindac Sulfide Scaffold

  摘要：

  Prostaglandins (PGs) are powerful lipid mediators in many physiological and pathophysiological responses. They are produced by oxidation of arachidonic acid (AA) by cyclo- oxygenases (COX-1 and COX-2) followed by metabolism of endoperoidde intermediates by terminal PG synthases. PG biosynthesis is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). Specific inhibition of COX-2 has been extensively investigated, but relatively few COX-1-selective inhibitors have been described. Recent reports of a possible contribution of COX-1 in analgesia, neuroinflammation, or carcinogenesis suggest that COX-1 is a potential therapeutic target. We designed, synthesized, and evaluated a series of (E)-2'-des-methyl-sulindac sulfide (E-DMSS) analogues for inhibition of COX-1. Several potent and selective inhibitors were discovered, and the most promising compounds were active against COX-1 in intact ovarian carcinoma cells (OVCAR-3). The compounds inhibited tumor cell proliferation but only at concentrations >100-fold higher than the concentrations that inhibit COX-1 activity. E-DMSS analogues may be useful probes of COX-1 biology in vivo and promising leads for COX-1-targeted therapeutic agents.

  DOI：

  10.1021/jm201528b

文献信息

• Indoleacetic acid and indenacetic acid derivatives as therapeutic agents with reduced gastrointestinal toxicity
  申请人：Marnett Lawrence J.

  公开号：US20090118290A1

  公开（公告）日：2009-05-07

  The presently disclosed subject matter provides derivatives of non-steroidal anti-inflammatory drugs (NSAIDs) that are characterized by substantially reduced cyclooxygenase inhibiting activity, yet retain the ability to interact with and modulate the activities of other polypeptides such as the class of peroxisome proliferators-activated receptors (PPARs) and γ-secretase. Also provided are methods of using the derivatives to treat pathological disorders.

  目前公开的主题提供了非甾体类抗炎药（NSAIDs）的衍生物，其特征是具有显著降低的环氧合酶抑制活性，但仍保留与其他多肽相互作用和调节活性的能力，如过氧化物酶体增殖物激活受体（PPARs）和γ-分泌酶。还提供了使用这些衍生物治疗病理性疾病的方法。
• Sulindac Derivatives That Activate the Peroxisome Proliferator-activated Receptor γ but Lack Cyclooxygenase Inhibition
  作者：Andrew S. Felts、Brianna S. Siegel、Shiu M. Young、Christopher W. Moth、Terry P. Lybrand、Andrew J. Dannenberg、Lawrence J. Marnett、Kotha Subbaramaiah

  DOI：10.1021/jm700969c

  日期：2008.8.1

  A series of novel derivatives of the nonsteroidal anti-inflammatory drug (NSAID) sulindac sulfide were synthesized as potential agonists of the peroxisome proliferator-activated receptor gamma (PPAR gamma). Nonpolar and aromatic substitutions oil the benzylidene ring as well as retention of the carboxylic acid side chain were required for optimal activity. Compound 24 was as potent a compound as my other in the series with,in EC(50) Of 0-1 mu M for the induction of peroxisome proliferator response element (PPRE)-luciferase activity. Direct binding of compound 24 to PPAR gamma was demonstrated by the displacement of I. 3 H]troglitazone, a PPAR gamma agonist, in a scintillation proximity assay. Compound 24 also stimulated the binding of PPAR gamma to a PPRE-containing oligonucleotide and induced expression of liver fatty-acid binding protein (L-FABP) and adipocyte fatty acid-binding protein (aP2), two established PPAR gamma target genes. Taken together, these compounds represent potential leads in the development of novel PPAR gamma agonists.
• US8168656B2
  申请人：——

  公开号：US8168656B2

  公开（公告）日：2012-05-01
• Cyclooxygenase-1-Selective Inhibitors Based on the (<i>E</i>)-2′-<i>Des</i>-methyl-sulindac Sulfide Scaffold
  作者：Andy J. Liedtke、Brenda C. Crews、Cristina M. Daniel、Anna L. Blobaum、Philip J. Kingsley、Kebreab Ghebreselasie、Lawrence J. Marnett

  DOI：10.1021/jm201528b

  日期：2012.3.8

  Prostaglandins (PGs) are powerful lipid mediators in many physiological and pathophysiological responses. They are produced by oxidation of arachidonic acid (AA) by cyclo- oxygenases (COX-1 and COX-2) followed by metabolism of endoperoidde intermediates by terminal PG synthases. PG biosynthesis is inhibited by nonsteroidal anti-inflammatory drugs (NSAIDs). Specific inhibition of COX-2 has been extensively investigated, but relatively few COX-1-selective inhibitors have been described. Recent reports of a possible contribution of COX-1 in analgesia, neuroinflammation, or carcinogenesis suggest that COX-1 is a potential therapeutic target. We designed, synthesized, and evaluated a series of (E)-2'-des-methyl-sulindac sulfide (E-DMSS) analogues for inhibition of COX-1. Several potent and selective inhibitors were discovered, and the most promising compounds were active against COX-1 in intact ovarian carcinoma cells (OVCAR-3). The compounds inhibited tumor cell proliferation but only at concentrations >100-fold higher than the concentrations that inhibit COX-1 activity. E-DMSS analogues may be useful probes of COX-1 biology in vivo and promising leads for COX-1-targeted therapeutic agents.