2,3-二羟基丙基(5Z,8Xi,13E)-11,15-二羟基-9-氧代前列腺-5,13-二烯-1-酸酯 | 37497-47-5

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 中文名称: 2,3-二羟基丙基(5Z,8Xi,13E)-11,15-二羟基-9-氧代前列腺-5,13-二烯-1-酸酯
• 英文名称: prostaglandin E2 1-glyceryl ester
• 英文别名: 2,3-dihydroxypropyl (Z)-7-[(1R,2R,3R)-3-hydroxy-2-[(E,3S)-3-hydroxyoct-1-enyl]-5-oxocyclopentyl]hept-5-enoate
• CAS: 37497-47-5
• 化学式: C₂₃H₃₈O₇
• 分子量: 426.5
• InChiKey: RJXVYMMSQBYEHN-LVXZDWGESA-N

物化性质

• 溶解度：
  DMF：10mg/mL； DMSO：10mg/mL；乙醇：10mg/mL； PBS（pH 7.2）：100 μg/ml

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  30
• 可旋转键数：
  16
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.74
• 拓扑面积：
  124
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  水 、 2,3-二羟基丙基(5Z,8Xi,13E)-11,15-二羟基-9-氧代前列腺-5,13-二烯-1-酸酯 生成 甘油 、 氢(+1)阳离子 、 prostaglandin E2(1-)
  参考文献：
  名称：

  活化的有机磷杀虫剂对人 THP1 单核细胞/巨噬细胞中脂质甘油酯代谢的灭活：羧酸酯酶 1 和 2 的作用

  摘要：

  羧酸酯酶 (CES) 在农药和药物代谢中具有重要作用，并有助于清除哺乳动物中含酯的异生物质。CES 表达水平最高的组织是肝脏和小肠。除了外源性物质，CES 还利用其广泛的底物特异性来水解内生素，例如胆固醇酯和甘油三酯。在这里，我们确定了两种人类 CES 亚型 CES1 和 CES2 是否水解内源性大麻素 2-花生四烯酸甘油 (2AG) 和花生四烯酸 (AEA)，以及两种前列腺素甘油酯 (PG-G)，它们是由 COX 介导的 2AG 氧化形成的. 我们表明重组 CES1 和 CES2 有效地将 2AG 水解为花生四烯酸 (AA)，但不能将含酰胺的 AEA 水解。CES1 和 CES2 介导的 2AG 水解的稳态动力学参数分别为，k cat , 59 和 43 min -1；K m，49 和 46 μM；和k cat / K m，1.2 和0.93 μM -1 min -1。k cat / K

  DOI：

  10.1021/tx1002194

文献信息

• PROSTAGLANDIN ANALOGS AND USES THEREOF
  申请人：Lifex Biolabs, Inc.

  公开号：US20210139435A1

  公开（公告）日：2021-05-13

  The present invention relates to pharmaceutical composition for the prevention or treatment of a disease, disorder, or condition associated with Nurr1, including, as an active ingredient, a prostaglandin analog or a pharmaceutically acceptable salt thereof, wherein the compound has excellent effects in inducing Nurr1, and thus, can be useful as a pharmaceutical composition for the prevention or treatment of a disease, disorder, or condition associated with Nurr1, in particular, cancer, autoimmune disease such as rheumatoid arthritis, schizophrenia, manic depression and neurodegenerative disease such as Alzheimers disease or Parkinson's disease.

  本发明涉及一种药物组合物，用于预防或治疗与Nurr1相关的疾病、紊乱或状况，其中包括作为活性成分的前列腺素类似物或其药学上可接受的盐，该化合物具有良好的诱导Nurr1的效果，因此，可用作预防或治疗与Nurr1相关的疾病、紊乱或状况的药物组合物，特别是癌症、自身免疫性疾病如类风湿关节炎、精神分裂症、躁郁症以及神经退行性疾病如阿尔茨海默病或帕金森病。
• Inactivation of Lipid Glyceryl Ester Metabolism in Human THP1 Monocytes/Macrophages by Activated Organophosphorus Insecticides: Role of Carboxylesterases 1 and 2
  作者：Shuqi Xie、Abdolsamad Borazjani、M. Jason Hatfield、Carol C. Edwards、Philip M. Potter、Matthew K. Ross

  DOI：10.1021/tx1002194

  日期：2010.12.20

  responsible for the hydrolysis of 2AG and PG-Gs in THP1 cells, although it did not rule out a role for other hydrolases, especially with regard to 2AG metabolism since a substantial portion of its hydrolysis was not inactivated by the inhibitors. An enzyme (Mr 31−32 kDa) of unknown function was detected by serine hydrolase activity profiling of THP1 cells and may be a candidate. Finally, the amounts of in

  羧酸酯酶 (CES) 在农药和药物代谢中具有重要作用，并有助于清除哺乳动物中含酯的异生物质。CES 表达水平最高的组织是肝脏和小肠。除了外源性物质，CES 还利用其广泛的底物特异性来水解内生素，例如胆固醇酯和甘油三酯。在这里，我们确定了两种人类 CES 亚型 CES1 和 CES2 是否水解内源性大麻素 2-花生四烯酸甘油 (2AG) 和花生四烯酸 (AEA)，以及两种前列腺素甘油酯 (PG-G)，它们是由 COX 介导的 2AG 氧化形成的. 我们表明重组 CES1 和 CES2 有效地将 2AG 水解为花生四烯酸 (AA)，但不能将含酰胺的 AEA 水解。CES1 和 CES2 介导的 2AG 水解的稳态动力学参数分别为，k cat , 59 和 43 min -1；K m，49 和 46 μM；和k cat / K m，1.2 和0.93 μM -1 min -1。k cat / K
• Hydrolysis of Prostaglandin Glycerol Esters by the Endocannabinoid-Hydrolyzing Enzymes, Monoacylglycerol Lipase and Fatty Acid Amide Hydrolase
  作者：Andrew Vila、Anja Rosengarth、Daniele Piomelli、Benjamin Cravatt、Lawrence J. Marnett

  DOI：10.1021/bi7005898

  日期：2007.8.1

  Cyclooxygenase-2 (COX-2) can oxygenate the endocannabinoids, arachidonyl ethanolamide (AEA) and 2-arachidonylglycerol (2-AG), to prostaglandin-H-2-ethanolamide (PGH(2)-EA) and -glycerol ester (PGH(2)-G), respectively. Further metabolism of PGH(2)-EA and PGH(2)-G by prostaglandin synthases produces a variety of prostaglandin-EA's and prostaglandin-G's nearly as diverse as those derived from arachidonic acid. Thus, COX-2 may regulate endocannabinoid levels in neurons during retrograde signaling or produce novel endocannabinoid metabolites for receptor activation. Endocannabinoid-metabolizing enzymes are important regulators of their action, so we tested whether PG-G levels may be regulated by monoacylglycerol lipase (MGL) and fatty acid amide hydrolase (FAAH). We found that PG-Gs are poor substrates for purified MGL and FAAH compared to 2-AG and/or AEA. Determination of substrate specificity demonstrates a 30-100- and 150-200-fold preference of MGL and FAAH for 2-AG over PG-Gs, respectively. The substrate specificity of AEA compared to those of PG-Gs was similar to 200-300 fold higher for FAAH. Thus, PG-Gs are poor substrates for the major endocannabinoid-degrading enzymes, MGL and FAAH.
• Identification of the Major Prostaglandin Glycerol Ester Hydrolase in Human Cancer Cells
  作者：Joseph D. Manna、James A. Wepy、Ku-Lung Hsu、Jae Won Chang、Benjamin F. Cravatt、Lawrence J. Marnett

  DOI：10.1074/jbc.m114.582353

  日期：2014.12

  Background: Prostaglandin glycerol esters are rapidly hydrolyzed in biological systems. Results: Complementary approaches demonstrated that lysophospholipase A2 hydrolyzes prostaglandin glycerol esters. Conclusion: Lysophospholipase A2 is a major prostaglandin glycerol ester-specific hydrolase in human cancer cells. Significance: Perturbation of lysophospholipase A2 provides a means to understand prostaglandin glycerol ester function in vivo.Prostaglandin glycerol esters (PG-Gs) are produced as a result of the oxygenation of the endocannabinoid, 2-arachidonoylglycerol, by cyclooxygenase 2. Understanding the role that PG-Gs play in a biological setting has been difficult because of their sensitivity to enzymatic hydrolysis. By comparing PG-G hydrolysis across human cancer cell lines to serine hydrolase activities determined by activity-based protein profiling, we identified lysophospholipase A2 (LYPLA2) as a major enzyme responsible for PG-G hydrolysis. The principal role played by LYPLA2 in PGE(2)-G hydrolysis was confirmed by siRNA knockdown. Purified recombinant LYPLA2 hydrolyzed PG-Gs in the following order of activity: PGE(2)-G > PGF(2)-G > PGD(2)-G; LYPLA2 hydrolyzed 1- but not 2-arachidonoylglycerol or arachidonoylethanolamide. Chemical inhibition of LYPLA2 in the mouse macrophage-like cell line, RAW264.7, elicited an increase in PG-G production. Our data indicate that LYPLA2 serves as a major PG-G hydrolase in human cells. Perturbation of this enzyme should enable selective modulation of PG-Gs without alterations in endocannabinoids, thereby providing a means to decipher the unique functions of PG-Gs in biology and disease.
• Mutation of Cys242 of Human Monoacylglycerol Lipase Disrupts Balanced Hydrolysis of 1- and 2-Monoacylglycerols and Selectively Impairs Inhibitor Potency
  作者：Tuomo Laitinen、Dina Navia-Paldanius、Roosa Rytilahti、Joona J. T. Marjamaa、Julie Kařízková、Teija Parkkari、Tatu Pantsar、Antti Poso、Jarmo T. Laitinen、Juha R. Savinainen

  DOI：10.1124/mol.113.090795

  日期：2014.3

  Considerable progress has been made in recent years in developing selective, potent monoacylglycerol lipase (MAGL) inhibitors. In the investigations of measures to inhibit this enzyme, less attention has been paid to improving our understanding of its catalytic mechanisms or substrate preferences. In our study, we used site-directed mutagenesis, and we show via versatile activity assays combined with molecular modeling that Cys242 and Tyr194, the two opposing amino acid residues in the catalytic cavity of MAGL, play important roles in determining the rate and the isomer preferences of monoacylglycerol hydrolysis. In contrast to wild-type enzymes that hydrolyzed 1- and 2-monoacylglycerols at similar rates, mutation of Cys242 to alanine caused a significant reduction in overall activity (maximal velocity, V max), particularly skewing the balanced hydrolysis of isomers to favor the 2-isomer. Molecular modeling studies indicate that this was caused by structural features unfavorable toward 1-isomers as well as impaired recognition of OH-groups in the glycerol moiety. Direct functional involvement of Cys242 in the catalysis was found unlikely due to the remote distance from the catalytic serine. Unlike C242A, mutation of Tyr194 did not bias the hydrolysis of 1- and 2-monoacylglycerols but significantly compromised overall activity. Finally, mutation of Cys242 was also found to impair inhibition of MAGL, especially that by fluorophosphonate derivatives (13- to 63-fold reduction in potency). Taken together, this study provides new experimental and modeling insights into the molecular mechanisms of MAGL-catalyzed hydrolysis of the primary endocannabinoid 2-arachidonoylglycerol and related monoacylglycerols.

  近年来，选择性、强效单酰基甘油酯酶（MAGL）抑制剂的研发取得了长足进展。在抑制这种酶的研究中，人们较少关注如何增进对酶催化机理或底物偏好的理解。在我们的研究中，我们采用了定点突变技术，并通过多功能活性测定与分子建模相结合的方法，证明了MAGL催化腔中两个相对的氨基酸残基Cys242和Tyr194在决定单酰基甘油酯水解速率和异构体偏好方面起着重要作用。与水解1-和2-单酰基甘油酯的速率相似的野生型酶相比，将Cys242突变为丙氨酸会导致总体活性（最大速度V max）显著降低，特别是使异构体的平衡水解偏向2-异构体。分子建模研究表明，这是由于结构特征不利于1-异构体，以及甘油部分中羟基的识别受损所致。由于与催化丝氨酸的距离较远，Cys242不太可能直接参与催化功能。与C242A不同，Tyr194突变不会影响1-和2-单酰基甘油酯的水解，但会显著降低总体活性。最后，还发现Cys242突变会削弱对MAGL的抑制作用，特别是氟磷酸酯衍生物的抑制作用（效力降低13至63倍）。总之，这项研究为MAGL催化