N-[(1,2-dihydro-8-methoxy-naphthalen-4-yl)-n-propyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline

• 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: N-[(1,2-dihydro-8-methoxy-naphthalen-4-yl)-n-propyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
• 英文别名: 6,7-dimethoxy-2-[3-(5-methoxy-3,4-dihydronaphthalen-1-yl)propyl]-3,4-dihydro-1H-isoquinoline
• 化学式: C₂₅H₃₁NO₃
• 分子量: 393.526
• InChiKey: BKLBMMUVHQYDCN-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  29
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  30.9
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  6,7-二甲氧基-1,2,3,4-四氢异喹啉 、 4-(3-溴-n-丙基)-1,2-二氢-8-甲氧基萘 在 sodium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 以90%的产率得到N-[(1,2-dihydro-8-methoxy-naphthalen-4-yl)-n-propyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
  参考文献：
  名称：

  Small P-gp modulating molecules: SAR studies on tetrahydroisoquinoline derivatives

  摘要：

  The development of small molecules as P-gp modulating agents and SAR studies on these ligands represented the aim of the present work. A series of 6,7-dimethoxytetrahydroisoquinoline derivatives was prepared and their ability to inhibit P-gp activity has been evaluated. The basic nucleus of these compounds, common to the best P-gp inhibitors such as Tariquidar and Elacridar, has been functionalized with no-basic moiety from our studied sigma receptor ligands displaying potent P-gp inhibition. The best results were obtained for compounds 3c and 3a (EC50 = 1.64 and 4.86 mu M, respectively) and these results were remarkable because Elacridar showed in the same biological evaluation similar inhibitory activity (EC50 = 2 mu M). SAR studies displayed that the removal of double bond on the spacer or its shifting into tetraline ring decreased the P-gp inhibiting activity. Moreover, the P-gp inhibition mechanism of tested compounds was investigated by three selected biological experiments. The results displayed that only compound 3c was P-gp inhibitor as Elacridar, while compound 3a and reference compounds Cyclosporin A and Verapamil modulated P-gp activity saturating the efflux pump as substrates. Flow cytometry studies carried out in Doxorubicin resistant breast cancer cell line (MCF7/Adr) confirmed that compound 3c increased Doxorubicin cell accumulation 5.7-fold. In addition, in MCF7/ Adr, antiproliferative effect of 5 mu M Doxorubicin shifted from 5% to 95% when co-administered with compound 3c (20 mu M). The present study suggested a new class of small molecules displaying P-gp inhibitor activity differing from reference compounds Elacridar and Tariquidar for a simplified, and in the meantime, efficacious no-basic moiety. (c) 2007 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2007.09.039

文献信息

• [EN] VERAPAMIL ANALOGUES WITH INHIBITION ACTIVITY ON ABC (ATP BINDING CASSETTE) CELL EXTRUSION PUMPS<br/>[FR] Analogues du vérapamil ayant une activité d'inhibition des pompes d'extrusion cellulaire d'ABC (cassette de liaison à l'ATP)
  申请人：ISTITUTO TUMORI GIOVANNI PAOLO

  公开号：WO2008017588A1

  公开（公告）日：2008-02-14

  [EN] The invention relates to a new class of compounds able to inhibit in a dose-dependent manner Glycoprotein-P (P-gp) activity in cell lines in which the expression of said glycoprotein is very high, like Caco-2 (human colon cancer) cells and MCF7/Adr (adriamycin-resistant human breast carcinoma) cells. The invention also relates to the use of such compounds as medicaments useful in the treatment of states linked to the difficulty for some drugs to cross the blood-brain barrier (BBB) and generally within the context of the problems of drug resistance induced by chemotherapy agents.
  [FR] L'invention concerne une nouvelle classe de composés capables d'inhiber de manière dépendante de la dose l'activité de la glycoprotéine P (P-gp) dans des lignées cellulaires dans lesquelles l'expression de cette glycoprotéine est très élevée, par exemple les cellules Caco-2 (cancer du côlon humain) et les cellules MCF7/Adr (cancer du sein humain résistant à l'adriamycine). L'invention concerne également l'utilisation de ces composés en tant que médicaments utiles dans le traitement d'états liés à la difficulté qu'ont certaines substances médicamenteuses à franchir la barrière hémato-encéphalique (BHE) et en général dans le contexte des problèmes de la résistance aux médicaments induite par des agents chimiothérapeutiques.
• Small P-gp modulating molecules: SAR studies on tetrahydroisoquinoline derivatives
  作者：Nicola Antonio Colabufo、Francesco Berardi、Mariangela Cantore、Maria Grazia Perrone、Marialessandra Contino、Carmela Inglese、Mauro Niso、Roberto Perrone、Amalia Azzariti、Grazia Maria Simone、Letizia Porcelli、Angelo Paradiso

  DOI：10.1016/j.bmc.2007.09.039

  日期：2008.1

  The development of small molecules as P-gp modulating agents and SAR studies on these ligands represented the aim of the present work. A series of 6,7-dimethoxytetrahydroisoquinoline derivatives was prepared and their ability to inhibit P-gp activity has been evaluated. The basic nucleus of these compounds, common to the best P-gp inhibitors such as Tariquidar and Elacridar, has been functionalized with no-basic moiety from our studied sigma receptor ligands displaying potent P-gp inhibition. The best results were obtained for compounds 3c and 3a (EC50 = 1.64 and 4.86 mu M, respectively) and these results were remarkable because Elacridar showed in the same biological evaluation similar inhibitory activity (EC50 = 2 mu M). SAR studies displayed that the removal of double bond on the spacer or its shifting into tetraline ring decreased the P-gp inhibiting activity. Moreover, the P-gp inhibition mechanism of tested compounds was investigated by three selected biological experiments. The results displayed that only compound 3c was P-gp inhibitor as Elacridar, while compound 3a and reference compounds Cyclosporin A and Verapamil modulated P-gp activity saturating the efflux pump as substrates. Flow cytometry studies carried out in Doxorubicin resistant breast cancer cell line (MCF7/Adr) confirmed that compound 3c increased Doxorubicin cell accumulation 5.7-fold. In addition, in MCF7/ Adr, antiproliferative effect of 5 mu M Doxorubicin shifted from 5% to 95% when co-administered with compound 3c (20 mu M). The present study suggested a new class of small molecules displaying P-gp inhibitor activity differing from reference compounds Elacridar and Tariquidar for a simplified, and in the meantime, efficacious no-basic moiety. (c) 2007 Elsevier Ltd. All rights reserved.