1-{4'-[(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)methyl]-[1,1'-biphenyl]-4-yl}-3-methylurea

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: 1-{4'-[(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)methyl]-[1,1'-biphenyl]-4-yl}-3-methylurea
• 英文别名: 1-[4-[4-[(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-yl)methyl]phenyl]phenyl]-3-methylurea
• 化学式: C₂₆H₂₉N₃O₃
• 分子量: 431.535
• InChiKey: APQJMFQVGOJLPM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  32
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  62.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  1-甲基-3-(4-溴苯基)脲 在 盐酸 、 palladium diacetate 、 三乙胺 、 二异丙胺 作用下， 以 水 、 乙腈 为溶剂， 反应 14.0h， 生成 1-{4'-[(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolin-2-yl)methyl]-[1,1'-biphenyl]-4-yl}-3-methylurea
  参考文献：
  名称：

  Design, Biological Evaluation, and Molecular Modeling of Tetrahydroisoquinoline Derivatives: Discovery of A Potent P-Glycoprotein Ligand Overcoming Multidrug Resistance in Cancer Stem Cells

  摘要：

  P-Glycoprotein is a well-known membrane transporter responsible for the efflux of an ample spectrum of anticancer drugs. Its relevance in the management of cancer chemotherapy is increased in view of its high expression in cancer stem cells, a population of cancer cells with strong tumor-promoting ability. In the present study, a series of compounds were synthesized through structure modulation of [4'-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-bipheny1-4-ol] (MC70), modifying the phenolic group of the lead compound. Among them, compound 513 emerged for its activity against the transporter (EC50 = 15 nM) and was capable of restoring doxorubicin antiproliferative activity at nontoxic concentration. Its behavior was rationalized through a molecular modeling study consisting of a well-tempered metadynamics simulation, which allowed one to identify the most favorable binding pose, and of a subsequent molecular dynamics run, which indicated a peculiar effect of the compound on the motion pattern of the transporter.

  DOI：

  10.1021/acs.jmedchem.8b01655

文献信息

• Design, Biological Evaluation, and Molecular Modeling of Tetrahydroisoquinoline Derivatives: Discovery of A Potent P-Glycoprotein Ligand Overcoming Multidrug Resistance in Cancer Stem Cells
  作者：Chiara Riganti、Marialessandra Contino、Stefano Guglielmo、Maria G. Perrone、Iris C. Salaroglio、Vladan Milosevic、Roberta Giampietro、Francesco Leonetti、Barbara Rolando、Loretta Lazzarato、Nicola A. Colabufo、Roberta Fruttero

  DOI：10.1021/acs.jmedchem.8b01655

  日期：2019.1.24

  P-Glycoprotein is a well-known membrane transporter responsible for the efflux of an ample spectrum of anticancer drugs. Its relevance in the management of cancer chemotherapy is increased in view of its high expression in cancer stem cells, a population of cancer cells with strong tumor-promoting ability. In the present study, a series of compounds were synthesized through structure modulation of [4'-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin-2-ylmethyl)-bipheny1-4-ol] (MC70), modifying the phenolic group of the lead compound. Among them, compound 513 emerged for its activity against the transporter (EC50 = 15 nM) and was capable of restoring doxorubicin antiproliferative activity at nontoxic concentration. Its behavior was rationalized through a molecular modeling study consisting of a well-tempered metadynamics simulation, which allowed one to identify the most favorable binding pose, and of a subsequent molecular dynamics run, which indicated a peculiar effect of the compound on the motion pattern of the transporter.