N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2-[(quinoline-2-carbonyl)-amino]-terephthalamic acid methyl ester | 1124227-79-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2-[(quinoline-2-carbonyl)-amino]-terephthalamic acid methyl ester
• 英文别名: methyl 4-((4-(2-(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl)phenyl)aminocarbonyl)-2-(quinoline-2-carbonylamino)benzoate；UR-ME22-1；Methyl 4-((4-(2-(6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl)phenyl)amino-carbonyl)-2-(quinoline-2-carbonylamino)benzoate；methyl 4-[[4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)ethyl]phenyl]carbamoyl]-2-(quinoline-2-carbonylamino)benzoate
• CAS: 1124227-79-7
• 化学式: C₃₈H₃₆N₄O₆
• 分子量: 644.727
• InChiKey: FCDNRJDHYPWDHC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.4
• 重原子数：
  48
• 可旋转键数：
  11
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  119
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2-[(quinoline-2-carbonyl)-amino]-terephthalamic acid trifluoroacetate 、 三甲基硅烷化重氮甲烷 以 甲醇 、 苯 为溶剂， 反应 1.0h， 以75%的产率得到N-{4-[2-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)-ethyl]-phenyl}-2-[(quinoline-2-carbonyl)-amino]-terephthalamic acid methyl ester
  参考文献：
  名称：

  Solid phase synthesis of tariquidar-related modulators of ABC transporters preferring breast cancer resistance protein (ABCG2)

  摘要：

  Aiming at structural optimization of potent and selective ABCG2 inhibitors, such as UR-ME22-1, from our laboratory, an efficient solid phase synthesis was developed to get convenient access to this class of compounds. 7-Carboxyisatoic anhydride was attached to Wang resin to give resin bound 2-aminoterephthalic acid. Acylation with quinoline-2- or -6-carbonyl chlorides, coupling with tetrahydroisoquinolinylethylphenylamine derivatives, cleavage of the carboxylic acids from solid support and treatment with trimethylsilydiazomethane gave the corresponding methyl esters. Among these esters highly potent and selective ABCG2 modulators were identified (inhibition of ABCB1 and ABCG2 determined in the calcein-AM and the Hoechst 33342 microplate assay, respectively). Interestingly, compounds bearing triethyleneglycol ether groups at the tetrahydroisoquinoline moiety (UR-COP77, UR-COP78) were comparable to UR-ME22-1 in potency but considerably more efficient (max inhibition 83% and 88% vs 60%, rel. to fumitremorgin c, 100%) These results support the hypothesis that solubility of the new ABCG2 modulators and of the reference compounds tariquidar and elacridar in aqueous media is the efficacy-limiting factor. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.04.094

文献信息

• Potent and Selective Inhibitors of Breast Cancer Resistance Protein (ABCG2) Derived from the <i>p</i>-Glycoprotein (ABCB1) Modulator Tariquidar
  作者：Matthias Kühnle、Michael Egger、Christine Müller、Anne Mahringer、Günther Bernhardt、Gert Fricker、Burkhard König、Armin Buschauer

  DOI：10.1021/jm8013822

  日期：2009.2.26

  ABCB1 (p-gp, MDR1) and ABCG2 (BCRP) are expressed to a high extent by endothelial cells at the blood−brain barrier (BBB) and other barrier tissues and are involved in drug resistance of tumor (stem) cells. Whereas numerous ABCB1 inhibitors are known, only a few ABCG2 modulators with submicromolar activity have been published. Starting from tariquidar (4) analogues as ABCB1 modulators, minimal structural

  外排泵ABCB1（p-gp，MDR1）和ABCG2（BCRP）在血脑屏障（BBB）和其他屏障组织中被内皮细胞大量表达，并参与肿瘤（干）细胞的耐药性。尽管已知许多ABCB1抑制剂，但仅公开了几种具有亚微摩尔活性的ABCG2调节剂。从作为ABCB1调节剂的tariquidar（4）类似物开始，最小的结构修饰导致急剧变化，有利于ABCG2抑制。最高效力发现当3,4-二甲氧基-2-（喹啉-3-羰基）苯甲酰基中部分4用4- methoxycarbonylbenzoyl部分带有hetarylcarboxamido组中的3位上，例如，喹啉-3-甲酰氨基（取代5，IC 50：119 nm）或喹啉-2-甲酰氨基（6，IC 50：60纳米，流式细胞米托蒽醌流出试验，拓扑替康耐MCF-7乳腺癌细胞）; ABCG2相对于ABCB1的选择性约为100-500倍，并且这些化合物对ABCC2（MRP2）无活性。针对MCF-7
• Solid phase synthesis of tariquidar-related modulators of ABC transporters preferring breast cancer resistance protein (ABCG2)
  作者：Cristian Ochoa Puentes、Peter Höcherl、Matthias Kühnle、Stefanie Bauer、Kira Bürger、Günther Bernhardt、Armin Buschauer、Burkhard König

  DOI：10.1016/j.bmcl.2011.04.094

  日期：2011.6

  Aiming at structural optimization of potent and selective ABCG2 inhibitors, such as UR-ME22-1, from our laboratory, an efficient solid phase synthesis was developed to get convenient access to this class of compounds. 7-Carboxyisatoic anhydride was attached to Wang resin to give resin bound 2-aminoterephthalic acid. Acylation with quinoline-2- or -6-carbonyl chlorides, coupling with tetrahydroisoquinolinylethylphenylamine derivatives, cleavage of the carboxylic acids from solid support and treatment with trimethylsilydiazomethane gave the corresponding methyl esters. Among these esters highly potent and selective ABCG2 modulators were identified (inhibition of ABCB1 and ABCG2 determined in the calcein-AM and the Hoechst 33342 microplate assay, respectively). Interestingly, compounds bearing triethyleneglycol ether groups at the tetrahydroisoquinoline moiety (UR-COP77, UR-COP78) were comparable to UR-ME22-1 in potency but considerably more efficient (max inhibition 83% and 88% vs 60%, rel. to fumitremorgin c, 100%) These results support the hypothesis that solubility of the new ABCG2 modulators and of the reference compounds tariquidar and elacridar in aqueous media is the efficacy-limiting factor. (C) 2011 Elsevier Ltd. All rights reserved.