4-<1-(4-fluorophenyl)-1H-indol-3-yl>-1-butanol methanesulfonate ester | 163630-97-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯
• 英文名称: 4-<1-(4-fluorophenyl)-1H-indol-3-yl>-1-butanol methanesulfonate ester
• 英文别名: 4-<1-(4-fluorophenyl)-1H-indol-3-yl>-1-butyl methanesulfonate；4-[1-(4-fluorophenyl)-1H-indol-3-yl]butyl-1-methanesulfonate；4-[1-(4-fluorophenyl)-1H-indol-3-yl]butyl methanesulfonate；4-[1-(4-Fluorophenyl)indol-3-yl]butyl methanesulfonate
• CAS: 163630-97-5
• 化学式: C₁₉H₂₀FNO₃S
• 分子量: 361.437
• InChiKey: FQHGSEVZRHHRMK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  25
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.26
• 拓扑面积：
  56.7
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3H-螺[2-苯并呋喃-1,4'-哌啶] 、 4-<1-(4-fluorophenyl)-1H-indol-3-yl>-1-butanol methanesulfonate ester 在 sodium carbonate 作用下， 以 水 、 丙酮 为溶剂， 生成 西拉美新
  参考文献：
  名称：

  吲哚与 4-[18F] 氟碘苯的 N-芳基化：合成用于正电子发射断层扫描 (PET) 的 18F 标记的 σ2 受体配体

  摘要：

  钯介导的吲哚与 4-[18F] 氟碘苯的 N-芳基化作为一种​​新的放射性标记方法已经开发出来。在吲哚与4-[18F]氟碘苯反应中，通过改变不同的催化剂体系（CuI/1,2-二胺和Pd2(dba)3/膦配体）、碱和溶剂来阐述优化的反应条件。优化的反应条件（Pd2(dba)3/(2-(dicyclohexyl-phosphino)-2'-(N,N-二甲氨基)-联苯、NaOBut、甲苯、100°C 20 min）用于合成18F -标记的 σ2 受体配体 [18F]-11 和 [18F]-13，分别以 91% 和 84% 的放射化学产率获得。版权所有 © 2004 John Wiley & Sons, Ltd.

  DOI：

  10.1002/jlcr.893
• 作为产物：
  描述：

  4-(吲哚-3-基)丁酸甲酯 在 N-甲基吡咯烷酮 、 copper(l) iodide 、 lithium aluminium tetrahydride 、 potassium carbonate 、 三乙胺 、 zinc(II) oxide 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 8.17h， 生成 4-<1-(4-fluorophenyl)-1H-indol-3-yl>-1-butanol methanesulfonate ester
  参考文献：
  名称：

  具有亚纳摩尔亲和力且对sigma 2结合位点优先的Sigma配体。1. 3-（ω-氨基烷基）-1H-吲哚。

  摘要：

  合成了一系列的4-（1H-吲哚-3-基）-1-丁基取代的4-苯基哌啶，4-苯基-1,2,3,6-四氢吡啶和4-苯基哌嗪。苯基任选地被4-氟或2-甲氧基取代基取代。用这些化合物实现了对sigma 1和sigma 2结合位点的高亲和力。另外，这些化合物对5-羟色胺5-HT1A和5-HT2A，多巴胺D2和肾上腺素α1受体具有较高的亲和力。在吲哚氮原子处引入4-氟苯基取代基使得对σ2结合位点具有亚纳摩尔亲和力的非常选择性的σ2配体。这种化合物的原型是1-（4-氟苯基）-3- [4- [4-（4-氟苯基）-1-哌啶基] -1-丁基] -1H-吲哚，11a（代码Lu 29） -253）。该化合物具有以下结合亲和力：IC50（sigma 1）= 16 nM，IC50（sigma 2）= 0.27 nM，IC50（5-HT1A）= 22,000 nM，IC50（5-HT2A）= 270 nM，IC50（D2）=

  DOI：

  10.1021/jm00011a019

文献信息

• .sigma. Ligands with Subnanomolar Affinity and Preference for the .sigma.2 Binding Site. 2. Spiro-Joined Benzofuran, Isobenzofuran, and Benzopyran Piperidines
  作者：Ejner K. Moltzen、Jens Perregaard、Eddi Meier

  DOI：10.1021/jm00011a020

  日期：1995.5

  structural factors governing sigma 1/sigma 2 affinity and selectivity within this class of compounds. The N-substituent in spiro[isobenzofuran-1(3H),4'-piperidines] is highly important, both for affinity and selectivity. Spiropiperidines with no or small N-substituents (H, Me, Et) exert very low affinity for both sigma 1 and sigma 2 binding sites (IC50(sigma 1, sigma 2) > 100 nM), whereas medium-sized substituents

  合成了螺[异苯并呋喃-1（3H），4'-哌啶]及相应的苯并呋喃和苯并吡喃衍生物，并作为σ配体进行了评估。这些化合物与Lu 28-179（1'-[4- [1-（4-氟苯基）-1H-吲哚-3-基] -1-丁基]螺[异苯并呋喃-1（3H），4'-哌啶]已被证明是选择性的sigma 2配体，其亲和力在亚纳摩尔范围内。该研究的目的是确定在这类化合物中控制sigma 1 / sigma 2亲和力和选择性的结构因素。螺[异苯并呋喃-1（3H），4'-哌啶]中的N-取代基对于亲和力和选择性都非常重要。没有或只有少量N取代基（H，Me，Et）的螺哌啶对sigma 1和sigma 2结合位点都具有非常低的亲和力（IC50（sigma 1，sigma 2）> 100 nM），而中等大小的取代基（例如Pr，Bu，Ph（CH2）2）会产生有效但非选择性的化合物（IC50（sigma 1，sigma 2）= 2-5
• Sigma-2 Receptor Agonists as Possible Antitumor Agents in Resistant Tumors: Hints for Collateral Sensitivity
  作者：Mauro Niso、Carmen Abate、Marialessandra Contino、Savina Ferorelli、Amalia Azzariti、Roberto Perrone、Nicola Antonio Colabufo、Francesco Berardi

  DOI：10.1002/cmdc.201300291

  日期：2013.12

  adenocarcinoma cells, with similar activity in the corresponding doxorubicin‐resistant MCF7adr cell line. Surprisingly, a few compounds, including 25, displayed enhanced activity in MCF7adr cells over parent cells, recalling the phenomenon of collateral sensitivity, which is under study for the treatment of drug‐resistant tumors. All of the compounds showed interaction with P‐glycoprotein (P‐gp), and 15

  与促进新的抗肿瘤剂的开发为目标，高亲和力σ 2受体激动剂被开发，用6,7-二甲氧基-2- [4- [1-（4-氟苯基）-1- ħ吲哚-3- [-基]丁基] -1,2,3,4-四氢异喹啉（15）和9- [4-（6,7-二甲氧基-1,2,3,4-四氢异喹啉-2-基）丁基] -9 H -咔唑（25）示出了特殊的选择性为σ 2亚型。大多数化合物在人MCF7乳腺腺癌细胞中显示出显着的抗增殖活性，在相应的对阿霉素耐药的MCF7adr细胞系中也具有相似的活性。令人惊讶的是，其中一些化合物包括25种，显示MCF7adr细胞的活性比亲代细胞增强，回想起附带敏感性的现象，该现象正在研究中，用于治疗耐药性肿瘤。所有这些化合物均显示与P-糖蛋白（P-gp）相互作用，而15和25具有最大的活性，能够逆转P-gp介导的耐药性，并重新建立阿霉素在MCF7adr细胞中的抗肿瘤作用。因此，我们确定了一系列σ的2赋有耐人寻味抗肿瘤特性受体激动剂;
• 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.
• 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.
• Substituted benzylaminoalkylindoles with preference for the σ2 binding site
  作者：Maria Grazia Mamolo、Daniele Zampieri、Caterina Zanette、Chiara Florio、Simona Collina、Mariangela Urbano、Ornella Azzolina、Luciano Vio

  DOI：10.1016/j.ejmech.2007.09.012

  日期：2008.10

  In the attempt to develop new sigma ligands we synthesized a series of N-benzyl-3-[1-(4-fluorophenyl)-1H-indol-3-yl]-N-methylpropan-1-amines and N-benzyl-4-[1-(4-fluorophenyl)-1H-indol-3-yl]-N-methylbutan-1-amines variously substituted on the phenyl ring. The displacement percentages of [H-3]-DTG and [H-3]-(+)-pentazocine determined in rat liver homogenates by these compounds at the fixed 100 nM concentration have been determined as a preliminary evaluation of their sigma(1) and sigma(2) affinity, respectively.The results suggested that the phenyl substituents may positively modulate, in comparison with the unsubstituted compound, the ability to displace [H-3]-DTG from sigma(2) sites, whereas the same phenyl substituents reduced the displacement percentages of [H-3]-(+)-pentazocine from sigma(1), sites. Some of these compounds were selected for radioligand binding assays. Compounds with a butylene intermediate chain displayed the greatest binding affinity for sigma(2) over sigma(1) receptors. The butylene derivative with 2,4-dimethyl substitution on the phenyl ring showed the greatest sigma(2) affinity (sigma K-2(i) = 5.9 nM) and an appreciable sigma(2) over sigma(1) selectivity (sigma K-1(i)/sigma K-2(i) = 22). The obtained results suggest that a butylene chain separating the indole moiety from variously substituted benzylamino groups may be required to their interaction with a hypothetical secondary sigma(2) binding site. (C) 2007 Elsevier Masson SAS. All rights reserved.