thiophosphoric acid O,O'-bis-(2-cyanoethyl) ester O''-tetradec-9-enyl ester | 849721-52-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 有机硫代磷酸及其衍生物
• 英文名称: thiophosphoric acid O,O'-bis-(2-cyanoethyl) ester O''-tetradec-9-enyl ester
• 英文别名: thiophosphoric acid O,O'-bis(2-cyanoethyl) ester O"-tetradec-9-enyl ester；3-[2-Cyanoethoxy(tetradec-9-enoxy)phosphinothioyl]oxypropanenitrile；3-[2-cyanoethoxy(tetradec-9-enoxy)phosphinothioyl]oxypropanenitrile
• CAS: 849721-52-4
• 化学式: C₂₀H₃₅N₂O₃PS
• 分子量: 414.549
• InChiKey: WXQQNHMRYWMNBY-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.4
• 重原子数：
  27
• 可旋转键数：
  19
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  107
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  双(2-氰乙基)-N,N-二异丙基亚磷酰胺 在 四氮唑 、 sulfur 作用下， 以 二氯甲烷 为溶剂， 反应 2.5h， 生成 thiophosphoric acid O,O'-bis-(2-cyanoethyl) ester O''-tetradec-9-enyl ester
  参考文献：
  名称：

  Synthesis, Structure−Activity Relationships, and Biological Evaluation of Fatty Alcohol Phosphates as Lysophosphatidic Acid Receptor Ligands, Activators of PPARγ, and Inhibitors of Autotaxin

  摘要：

  We previously reported that fatty alcohol phosphates (FAP) represent a minimal pharmacophore required to interact with lysophosphatidic acid (LPA) receptors. To improve the activity of the first-generation saturated FAP series, a structure-activity relationship (SAR) study was carried out that includes modifications to the headgroup and alkyl side chain of the FAP pharmacophore. A series of unsaturated (C-10-C-18) FAP, headgroup-modified hydrolytically stable saturated (C-10-C-18) alkyl phosphonates, and saturated and unsaturated (C-10-C-18) thiophosphate analogues were synthesized and evaluated for activity in RH7777 cells transfected with individual LPA(1-3) receptors, in PC-3 cells and in human platelets that endogenously express all three isoforms. In this series we identified several LPA(1)- and LPA(3)-selective antagonists with IC50 values in the nanomolar range. Oleoyl-thiophosphate (15g) was shown to be a panagonist, whereas tetradecyl-phosphonate (16c) was identified as a pan-antagonist. These compounds were also tested for the ability to activate the transcription factor PPAR gamma, an intracellular receptor for LPA, in CV1 cells transfected with the PPRE-Acox-Rluc reporter gene. All the FA-P tested, along with the previously reported LPA GPCR antagonists dioctanoyl glycerol pyrophosphate (2), Ki16425 (6), and the agonist OMPT (3), were activators of PPAR gamma. The pan-agonist oleoyl-thiophosphate (15g) and pan-antagonist tetradecyl-phosphonate (16c) mimicked LPA in inhibiting autotaxin, a secreted lysophospholipase D that produces LPA in biological fluids.

  DOI：

  10.1021/jm049609r

文献信息

• Synthesis, Structure−Activity Relationships, and Biological Evaluation of Fatty Alcohol Phosphates as Lysophosphatidic Acid Receptor Ligands, Activators of PPARγ, and Inhibitors of Autotaxin
  作者：Gangadhar G. Durgam、Tamas Virag、Michelle D. Walker、Ryoko Tsukahara、Satoshi Yasuda、Karoly Liliom、Laurens A. van Meeteren、Wouter H. Moolenaar、Nicole Wilke、Wolfgang Siess、Gabor Tigyi、Duane D. Miller

  DOI：10.1021/jm049609r

  日期：2005.7.1

  We previously reported that fatty alcohol phosphates (FAP) represent a minimal pharmacophore required to interact with lysophosphatidic acid (LPA) receptors. To improve the activity of the first-generation saturated FAP series, a structure-activity relationship (SAR) study was carried out that includes modifications to the headgroup and alkyl side chain of the FAP pharmacophore. A series of unsaturated (C-10-C-18) FAP, headgroup-modified hydrolytically stable saturated (C-10-C-18) alkyl phosphonates, and saturated and unsaturated (C-10-C-18) thiophosphate analogues were synthesized and evaluated for activity in RH7777 cells transfected with individual LPA(1-3) receptors, in PC-3 cells and in human platelets that endogenously express all three isoforms. In this series we identified several LPA(1)- and LPA(3)-selective antagonists with IC50 values in the nanomolar range. Oleoyl-thiophosphate (15g) was shown to be a panagonist, whereas tetradecyl-phosphonate (16c) was identified as a pan-antagonist. These compounds were also tested for the ability to activate the transcription factor PPAR gamma, an intracellular receptor for LPA, in CV1 cells transfected with the PPRE-Acox-Rluc reporter gene. All the FA-P tested, along with the previously reported LPA GPCR antagonists dioctanoyl glycerol pyrophosphate (2), Ki16425 (6), and the agonist OMPT (3), were activators of PPAR gamma. The pan-agonist oleoyl-thiophosphate (15g) and pan-antagonist tetradecyl-phosphonate (16c) mimicked LPA in inhibiting autotaxin, a secreted lysophospholipase D that produces LPA in biological fluids.