3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propanoic acid | 861892-56-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 四氢化萘
• 英文名称: 3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propanoic acid
• CAS: 861892-56-0
• 化学式: C₁₄H₁₈O₃
• 分子量: 234.295
• InChiKey: VVSTYMZPGCTJGD-UHFFFAOYSA-N

物化性质

• 沸点：
  412.6±38.0 °C(Predicted)
• 密度：
  1.121±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  17
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  46.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propanoic acid 在 N,N-二甲基甲酰胺 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 生成 4-(4-cyclohexyl)-1-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperidine
  参考文献：
  名称：

  Potential applications for sigma receptor ligands in cancer diagnosis and therapy

  摘要：

  Sigma receptors (sigma-1 and sigma-2) represent two independent classes of proteins. Their endogenous ligands may include the hallucinogen N,N-dimethyltryptamine (DMT) and sphingolipid-derived amines which interact with sigma-1 receptors, besides steroid hormones (e.g., progesterone) which bind to both sigma receptor sub-populations. The sigma-1 receptor is a ligand-regulated molecular chaperone with various ion channels and G-protein-coupled membrane receptors as clients. The sigma-2 receptor was identified as the progesterone receptor membrane component 1 (PGRMC1). Although sigma receptors are over-expressed in tumors and up-regulated in rapidly dividing normal tissue, their ligands induce significant cell death only in tumor tissue. Sigma ligands may therefore be used to selectively eradicate tumors. Multiple mechanisms appear to underlie cell killing after administration of sigma ligands, and the signaling pathways are dependent both on the type of ligand and the type of tumor cell. Recent evidence suggests that the sigma-2 receptor is a potential tumor and serum biomarker for humaniung cancer and an important target for inhibiting tumor invasion and cancer progression. Current radiochemical efforts are focused on the development of subtype-selective radioligands for positron emission tomography (PET) imaging. Right now, the mostpromising tracers are [F-18]fluspidine and [F-18]FTC-146 for sigma-1 receptors and [C-11]RHM-1 and [F-18]ISO-1 for the sigma-2 subtype. Nanoparticles coupled to sigma ligands have shown considerable potential for targeted delivery of antitumor drugs in animal models of cancer, but clinical studies exploring this strategy in cancer patients have not yet been reported. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. (C) 2014 Elsevier B.V. All rights reserved.

  DOI：

  10.1016/j.bbamem.2014.08.022
• 作为产物：
  描述：

  3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propanoic acid ethyl ester 在 水 、 sodium hydroxide 作用下， 生成 3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propanoic acid
  参考文献：
  名称：

  Exploring the Importance of Piperazine N-Atoms for σ₂ Receptor Affinity and Activity in a Series of Analogs of 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28)

  摘要：

  sigma(2)-Agonist 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (7, PB 28), which proved to revert doxorubicin resistance in breast cancer cells, was taken as a template to prepare new analogs. One of the two basic N-atoms wits alternatively replaced by it methine or converted into an amide or ammonium function, with the aim of finding out which of them was essential For sigma(2) receptor affinity and activity. Some simply 4-substituted 1-cyclohexylpiperazines were also investigated. None of the compounds was as high-affinity as 7 (sigma K-2(i) = 0.68, sigma K-1(i) = 0.38 nM), proving that both basic N-atoms ensure better sigma(2) receptor binding. Amide 36 emerged as high-affinity (K-i = 0.11 nM) and noteworthy selective (1627-fold) or, ligand. Small N-cyclohexylpiperazine 59 displayed the highest sigma(2) affinity (K-i = 4.70 nM). The sigma(2)/sigma(1) selectivities were generally low. Antiproliferative assay in SK-N-SH cells revealed piperidines 24 and 15 as putative sigma(2), agonists (EC(50)s 1.40 and 3.64 mu M respectively) more potent than 7.

  DOI：

  10.1021/jm9007505

文献信息

• [EN] TRITIUM RADIOLABELING OF [3H]-1-CYCLOHEXYL-4-[3-(5-METHOXY-1,2, 3,4,-TETRAHYDRONAPHTHALEN-1-YL)-N-PROPYL]PIPERAZINE ([3H]-PB28), AS A POTENT SIGMA-2 RECEPTOR LIGAND<br/>[FR] RADIOMARQUAGE AU TRITIUM DE [3H]-1-CYCLOHEXYL-4-[3-(5- MÉTHOXY-1,2,3,4-TÉTRAHYDRONAPHTALÈN-1-YL)-N-PROPYL]PIPÉRAZINE ([3H]-PB28), EN TANT QUE LIGAND EFFICACE DES RÉCEPTEURS SIGMA-2
  申请人：UNIV BARI

  公开号：WO2009104058A1

  公开（公告）日：2009-08-27

  The invention relates to a novel process for the radiolabeling with [3H] of the l-cyclohexyl-4- [3- (5- methoxy-1, 2,3,4, -tetrahydronaphthalen-1-yl) -n- propyl]piperazine (PB28) ligand of formula 1 and enantiomeric forms thereof, specific for the sigma-2 receptors. The invention further relates to the same radiolabeled ligand and to its use as a highly selective analytical instrument in the evaluation of the expression levels of said receptors in tissues, as selection tool of novel specific ligands, and as diagnostic agent in diagnostic kits.

  该发明涉及一种新型方法，用于对公式1中的l-环己基-4-[3-(5-甲氧基-1,2,3,4,-四氢萘基)-n-丙基]哌嗪（PB28）配体进行[3H]放射标记，以及其对映体形式，特异于sigma-2受体。该发明还涉及同一放射标记的配体及其用途，作为在组织中评估所述受体表达水平的高度选择性分析仪器，作为新型特异性配体的选择工具，并作为诊断试剂盒中的诊断试剂。
• From mixed sigma-2 receptor/P-glycoprotein targeting agents to selective P-glycoprotein modulators: Small structural changes address the mechanism of interaction at the efflux pump
  作者：Carmen Abate、Maria Laura Pati、Marialessandra Contino、Nicola Antonio Colabufo、Roberto Perrone、Mauro Niso、Francesco Berardi

  DOI：10.1016/j.ejmech.2014.10.082

  日期：2015.1

  Generations of modulators of the efflux pump P-glycoprotein (P-gp) have been produced as tools to counteract the Multidrug Resistance (MDR) phenomenon in tumor therapy, but clinical trials were not successful so far. With the aim of contributing to the development of novel P-gp modulators, we started from recently studied high-affinity sigma-2 (sigma(2)) receptor ligands that showed also potent interaction with P-gp. For sigma(2) receptors high-affinity binding, a basic N-atom is a strict requirement. Therefore, we reduced the basic character of the N-atom present in these ligands, and we obtained potent P-gp modulators with poor or null sigma(2) receptor affinity. We also evaluated whether modulation of P-gp by these novel compounds involved consumption of ATP (as P-gp substrates do), as a source of energy to support the efflux. Surprisingly, even small structural changes resulted in opposite behavior, with amide 13 depleting ATP, in contrast to its isomer 18. Two compounds, 15 and 25, emerged for their potent activity at P-gp, and deserve further investigations as tools for P-gp modulation. (C) 2014 Elsevier Masson SAS. All rights reserved.
• Exploring the Importance of Piperazine N-Atoms for σ₂ Receptor Affinity and Activity in a Series of Analogs of 1-Cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (PB28)
  作者：Francesco Berardi、Carmen Abate、Savina Ferorelli、Vincenzo Uricchio、Nicola A. Colabufo、Mauro Niso、Roberto Perrone

  DOI：10.1021/jm9007505

  日期：2009.12.10

  sigma(2)-Agonist 1-cyclohexyl-4-[3-(5-methoxy-1,2,3,4-tetrahydronaphthalen-1-yl)propyl]piperazine (7, PB 28), which proved to revert doxorubicin resistance in breast cancer cells, was taken as a template to prepare new analogs. One of the two basic N-atoms wits alternatively replaced by it methine or converted into an amide or ammonium function, with the aim of finding out which of them was essential For sigma(2) receptor affinity and activity. Some simply 4-substituted 1-cyclohexylpiperazines were also investigated. None of the compounds was as high-affinity as 7 (sigma K-2(i) = 0.68, sigma K-1(i) = 0.38 nM), proving that both basic N-atoms ensure better sigma(2) receptor binding. Amide 36 emerged as high-affinity (K-i = 0.11 nM) and noteworthy selective (1627-fold) or, ligand. Small N-cyclohexylpiperazine 59 displayed the highest sigma(2) affinity (K-i = 4.70 nM). The sigma(2)/sigma(1) selectivities were generally low. Antiproliferative assay in SK-N-SH cells revealed piperidines 24 and 15 as putative sigma(2), agonists (EC(50)s 1.40 and 3.64 mu M respectively) more potent than 7.
• Potential applications for sigma receptor ligands in cancer diagnosis and therapy
  作者：Aren van Waarde、Anna A. Rybczynska、Nisha K. Ramakrishnan、Kiichi Ishiwata、Philip H. Elsinga、Rudi A.J.O. Dierckx

  DOI：10.1016/j.bbamem.2014.08.022

  日期：2015.10

  Sigma receptors (sigma-1 and sigma-2) represent two independent classes of proteins. Their endogenous ligands may include the hallucinogen N,N-dimethyltryptamine (DMT) and sphingolipid-derived amines which interact with sigma-1 receptors, besides steroid hormones (e.g., progesterone) which bind to both sigma receptor sub-populations. The sigma-1 receptor is a ligand-regulated molecular chaperone with various ion channels and G-protein-coupled membrane receptors as clients. The sigma-2 receptor was identified as the progesterone receptor membrane component 1 (PGRMC1). Although sigma receptors are over-expressed in tumors and up-regulated in rapidly dividing normal tissue, their ligands induce significant cell death only in tumor tissue. Sigma ligands may therefore be used to selectively eradicate tumors. Multiple mechanisms appear to underlie cell killing after administration of sigma ligands, and the signaling pathways are dependent both on the type of ligand and the type of tumor cell. Recent evidence suggests that the sigma-2 receptor is a potential tumor and serum biomarker for humaniung cancer and an important target for inhibiting tumor invasion and cancer progression. Current radiochemical efforts are focused on the development of subtype-selective radioligands for positron emission tomography (PET) imaging. Right now, the mostpromising tracers are [F-18]fluspidine and [F-18]FTC-146 for sigma-1 receptors and [C-11]RHM-1 and [F-18]ISO-1 for the sigma-2 subtype. Nanoparticles coupled to sigma ligands have shown considerable potential for targeted delivery of antitumor drugs in animal models of cancer, but clinical studies exploring this strategy in cancer patients have not yet been reported. This article is part of a Special Issue entitled: Membrane channels and transporters in cancers. (C) 2014 Elsevier B.V. All rights reserved.