2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)acetonitrile | 160446-14-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)acetonitrile
• 英文别名: (6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)acetonitrile；2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)acetonitrile
• CAS: 160446-14-0
• 化学式: C₁₃H₁₆N₂O₂
• mdl: MFCD02058491
• 分子量: 232.282
• InChiKey: SXRFKBWAUGWXIS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.461
• 拓扑面积：
  45.5
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)acetonitrile 在 lithium aluminium tetrahydride 、 1-羟基苯并三唑 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 4.0h， 生成 N-(2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl)-1-(4-methoxyphenyl)-1H-1,2,3-triazole-4-carboxamide
  参考文献：
  名称：

  Synthesis and Structure–Activity Relationship Studies of Conformationally Flexible Tetrahydroisoquinolinyl Triazole Carboxamide and Triazole Substituted Benzamide Analogues as σ₂ Receptor Ligands

  摘要：

  Two novel classes of compounds targeting the sigma-2 (sigma(2)) receptor were synthesized, and their bioactivities to binding sigma(1) and sigma(2) receptors were measured. Four novel triazole carboxamide analogues, 24d, 24e, 24f, and 39c, demonstrated high affinity and selectivity for the sigma(2) receptor. These data suggest C-11-labeled versions of these compounds may be potential sigma(2)-selective radiotracers for imaging the proliferative status of solid tumors.

  DOI：

  10.1021/jm5001453
• 作为产物：
  描述：

  3,4-二甲氧基苯乙胺 在 三乙胺 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 反应 19.0h， 生成 2-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)acetonitrile
  参考文献：
  名称：

  基于结构的嘧啶氨基苯衍生物作为对抗P-gp和BCRP介导的多药耐药性的有效口服逆转剂的发现

  摘要：

  包括P-糖蛋白（P-gp）和乳腺癌抗性蛋白（BCRP）在内的ATP结合盒（ABC）转运蛋白的过表达是导致癌症治疗中多药抗性（MDR）的重要因素。基于BCRP抑制剂，酪氨酸激酶抑制剂和P-gp抑制剂的活性部分，设计了P-gp和BCRP双重抑制剂的三个亚类，其中化合物21具有低细胞毒性，高逆转效能和良好的脂质分布系数。21还增加了阿霉素（ADM）和米托蒽醌（MX）的积累，阻止Rh123流出，并且P-gp和BCRP的蛋白质表达没有变化。重要的是，共同管理21可以显着提高紫杉醇（PTX）的口服生物利用度。还表明，21可通过增加体内ADM的敏感性来显着抑制K562 / A02异种移植瘤的生长。总之，21有潜力克服由P-gp和BCRP引起的MDR，并提高PTX的口服生物利用度。

  DOI：

  10.1021/acs.jmedchem.1c00246

文献信息

• ^99mTc-Cyclopentadienyl Tricarbonyl Chelate-Labeled Compounds as Selective Sigma-2 Receptor Ligands for Tumor Imaging
  作者：Dan Li、Yuanyuan Chen、Xia Wang、Winnie Deuther-Conrad、Xin Chen、Bing Jia、Chengyan Dong、Jörg Steinbach、Peter Brust、Boli Liu、Hongmei Jia

  DOI：10.1021/acs.jmedchem.5b01378

  日期：2016.2.11

  receptor affinity (Ki = 2.97 nM) and moderate subtype selectivity (10-fold). Moreover, it showed high selectivity toward vesicular acetylcholine transporter (2374-fold), dopamine D2L receptor, NMDA receptor, opiate receptor, dopamine transporter, norepinephrine transporter, and serotonin transporter. Its corresponding radiotracer [99mTc]20b showed high uptake in a time- and dose-dependent manner in DU145

  我们设计并合成了含有5,6- dimethoxyisoindoline或6,7-二甲氧基-1,2,3,4-四氢异喹啉作为药效σ一系列环戊二烯基三羰基铼配合2受体配体。铼化合物20A具有低纳摩尔σ 2受体的亲和力（ķ我= 2.97 nM）的和中度的亚型选择性（10倍）。此外，它对水泡乙酰胆碱转运蛋白（2374倍），多巴胺D 2L受体，NMDA受体，阿片受体，多巴胺转运蛋白，去甲肾上腺素转运蛋白和5-羟色胺转运蛋白显示出很高的选择性。其相应的放射性示踪剂[ 99m Tc] 20b在DU145前列腺细胞和C6胶质瘤细胞中显示出高吸收，呈时间和剂量依赖性。此外，该示踪剂在裸鼠中显示出高的肿瘤吸收率（在240分钟时为5.92％ID / g）和高的肿瘤/血液和肿瘤/肌肉比率（在240分钟时分别为21和16）以及与σ受体的特异性结合带有C6胶质瘤异种移植物。C6胶质瘤异种移植模型中[ 99m Tc] 20b的小动物SPECT
• Discovery of (quinazolin-6-yl)benzamide derivatives containing a 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety as potent reversal agents against P-glycoprotein-mediated multidrug resistance
  作者：Wen-han Xue、Kai-li Liu、Ting-jian Zhang、Gang Dong、Jia-hui Wang、Jing Wang、Shuai Guo、Jie Hu、Qing-yu Zhang、Xin-yang Li、Fan-hao Meng

  DOI：10.1016/j.ejmech.2023.116039

  日期：2024.1

  P-glycoprotein (P-gp) is an important factor leading to multidrug resistance (MDR) in cancer treatment. The co-administration of anticancer drugs and P-gp inhibitors has been a treatment strategy to overcome MDR. In recent years, tyrosine kinase inhibitor Lapatinib has been reported to reverse MDR through directly interacting with ABC transporters. In this work, a series of P-gp inhibitors (1–26) was

  P-糖蛋白（P-gp）是癌症治疗中导致多药耐药（MDR）的重要因素。抗癌药物和P-gp抑制剂联合给药一直是克服MDR的治疗策略。近年来，酪氨酸激酶抑制剂拉帕替尼被报道可通过与ABC转运蛋白直接相互作用来逆转MDR。本工作通过将拉帕替尼的喹唑啉核心整合到第三代P-gp抑制剂Tariquidar的分子框架中，设计合成了一系列P-gp抑制剂（ 1-26 ）。其中，化合物14表现出比Tariquidar更好的MDR逆转活性。对接结果显示化合物14呈现L型分子构象。重要的是，化合物14增加了MCF7/ADM 细胞中阿霉素 (ADM) 和罗丹明 123 (Rh123) 的积累。此外，化合物14显着增加ADM诱导的细胞凋亡并抑制MCF7/ADM细胞的增殖、迁移和侵袭。还证明化合物14通过增加ADM的敏感性而显着抑制MCF7/ADM异种移植肿瘤的生长。综上所述，化合物14具有克服P-gp引起的MDR的潜力。
• In vitro activity of novel dual action MDR anthranilamide modulators with inhibitory activity at CYP-450
  作者：Philippe Labrie、Shawn. P. Maddaford、Jacques Lacroix、Concettina Catalano、David K.H. Lee、Suman Rakhit、René C. Gaudreault

  DOI：10.1016/j.bmc.2006.07.055

  日期：2006.12

  Synthesis and in vitro cytotoxicity assays of new anthranilamide MDR modulators have been performed to assess their inhibition potency of the P-glycoprotein (P-gp) transporter. The aromatic spacer group between nitrogen atoms (N1 and N2) in the known inhibitor XR9576 was replaced with a flexible alkyl chain of 2 to 6 carbon atoms in length. 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline and their open-chain N-methylhomoveratrylamine counterparts were shown to be potent P-gp inhibitors. The maximal inhibition was obtained when using an ethyl or propyl spacer. Several compounds were more potent than verapamil and intrinsically less cytotoxic than XR9576. In addition, in vitro metabolism studies of 23a with a subset of human CYP-450 isoforms revealed that, unlike XR9576, 23a inhibited CYP3A4, an enzyme that colocalizes with P-gp in the intestine and contributes to tumor cell chemoresistance by enhancing the biodisposition of anticancer drugs such as paclitaxel toward metabolism. In this context, 22a might be a suitable candidate for further drug development.
• Conformationally-flexible benzamide analogues as dopamine D3 and σ2 receptor ligands
  作者：Robert H Mach、Yunsheng Huang、Rebekah A Freeman、Li Wu、Suwanna Vangveravong、Robert R Luedtke

  DOI：10.1016/j.bmcl.2003.09.083

  日期：2004.1

  A series of conformationally-flexible analogues was prepared and their affinities for D2-like dopamine(D-2, D-3 and D-4) were determined using in vitro radioligand binding assays. The results of this structure-activity relationship study identified one compound, 15, that bound with high affinity (K-i value = 2 nM) and moderate selectivity (30-fold) for D-3 compared to D-2 receptors. In addition, this series of compounds were also tested for affinity at sigma(1) and sigma(2) receptors. We evaluated the affinity of these dopaminergic compounds at sigma receptors because (a) several antipsychotic drugs, which are high affinity antagonists at dopamine D2-like receptors, also bind to sigma receptors and (b) sigma receptors are expressed ubiquitously and at high levels (picomoles per mg proteins). It was observed that a number of analogues displayed high affinity and excellent selectivity for sigma(2) versus sigma(1) receptors. Consequently, these novel compounds may be useful for characterizing the functional role of sigma(2) receptors and for imaging the sigma(2) receptor status of tumors in vivo with PET. (C) 2003 Elsevier Ltd. All rights reserved.
• US5294621A
  申请人：——

  公开号：US5294621A

  公开（公告）日：1994-03-15