(S)-3-((R)-9-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-7-hydroxy-6-methoxyisobenzofuran-1(3H)-one

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 邻苯二甲酸异喹啉类
• 英文名称: (S)-3-((R)-9-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-7-hydroxy-6-methoxyisobenzofuran-1(3H)-one
• 英文别名: 9-bromo-7-hydroxynoscapine；(3S)-3-[(5R)-9-bromo-4-methoxy-6-methyl-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-5-yl]-7-hydroxy-6-methoxy-3H-2-benzofuran-1-one
• 化学式: C₂₁H₂₀BrNO₇
• 分子量: 478.296
• InChiKey: WDEDSCMYWUIVOF-WBVHZDCISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  30
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  86.7
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (S)-3-((R)-9-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-7-hydroxy-6-methoxyisobenzofuran-1(3H)-one 、 (3-溴丙基)三甲基溴化铵 在 potassium carbonate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 以70%的产率得到3-(((S)-1-((R)-9-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-5-methoxy-3-oxo-1,3-dihydroisobenzofuran-4-yl)oxy)-N,N,N-trimethylpropan-1-aminium bromide
  参考文献：
  名称：

  Novel third-generation water-soluble noscapine analogs as superior microtubule-interfering agents with enhanced antiproliferative activity

  摘要：

  Noscapine, an opium-derived 'kinder-gentler' microtubule-modulating drug is in Phase I/II clinical trials for cancer chemotherapy. However, its limited water solubility encumbers its development into an oral anticancer drug with clinical promise. Here we report the synthesis of 9 third-generation, water-soluble noscapine analogs with negatively charged sulfonato and positively charged quaternary ammonium groups using noscapine, 9-bromonoscapine and 9-aminonoscapine as scaffolds. The predictive free energy of solvation was found to be lower for sulfonates (6a-c; 8a-c) compared to the quaternary ammonium-substituted counterparts, explaining their higher water solubility. In addition, sulfonates showed higher charge dispersability, which may effectively shield the hydrophobicity of isoquinoline nucleus as indicated by hydrophobicity mapping methods. These in silico data underscore efficient net charge balancing, which may explain higher water solubility and thus enhanced antiproliferative efficacy and improved bioavailability. We observed that 6b, 8b and Sc strongly inhibited tubulin polymerization and demonstrated significant antiproliferative activity against four cancer cell lines compared to noscapine. Molecular simulation and docking studies of tubulin-drug complexes revealed that the brominated compound with a four-carbon chain (4b, 6b, and 8b) showed optimal binding with tubulin heterodimers. Interestingly, 6b, 8b and Sc treated PC-3 cells resulted in preponderance of mitotic cells with multipolar spindle morphology, suggesting that they stall the cell cycle. Furthermore, in vivo pharmacokinetic evaluation of 6b, 8b and Sc revealed at least 1-2-fold improvement in their bioavailability compared to noscapine. To our knowledge, this is the first report to demonstrate novel water-soluble noscapine analogs that may pave the way for future pre-clinical drug development. (C) 2014 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2014.07.020
• 作为产物：
  描述：

  那可汀 在 sodium azide 、 氢溴酸 、 溴 、 sodium iodide 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 (S)-3-((R)-9-bromo-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-7-hydroxy-6-methoxyisobenzofuran-1(3H)-one
  参考文献：
  名称：

  Novel third-generation water-soluble noscapine analogs as superior microtubule-interfering agents with enhanced antiproliferative activity

  摘要：

  Noscapine, an opium-derived 'kinder-gentler' microtubule-modulating drug is in Phase I/II clinical trials for cancer chemotherapy. However, its limited water solubility encumbers its development into an oral anticancer drug with clinical promise. Here we report the synthesis of 9 third-generation, water-soluble noscapine analogs with negatively charged sulfonato and positively charged quaternary ammonium groups using noscapine, 9-bromonoscapine and 9-aminonoscapine as scaffolds. The predictive free energy of solvation was found to be lower for sulfonates (6a-c; 8a-c) compared to the quaternary ammonium-substituted counterparts, explaining their higher water solubility. In addition, sulfonates showed higher charge dispersability, which may effectively shield the hydrophobicity of isoquinoline nucleus as indicated by hydrophobicity mapping methods. These in silico data underscore efficient net charge balancing, which may explain higher water solubility and thus enhanced antiproliferative efficacy and improved bioavailability. We observed that 6b, 8b and Sc strongly inhibited tubulin polymerization and demonstrated significant antiproliferative activity against four cancer cell lines compared to noscapine. Molecular simulation and docking studies of tubulin-drug complexes revealed that the brominated compound with a four-carbon chain (4b, 6b, and 8b) showed optimal binding with tubulin heterodimers. Interestingly, 6b, 8b and Sc treated PC-3 cells resulted in preponderance of mitotic cells with multipolar spindle morphology, suggesting that they stall the cell cycle. Furthermore, in vivo pharmacokinetic evaluation of 6b, 8b and Sc revealed at least 1-2-fold improvement in their bioavailability compared to noscapine. To our knowledge, this is the first report to demonstrate novel water-soluble noscapine analogs that may pave the way for future pre-clinical drug development. (C) 2014 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2014.07.020

文献信息

• Synthesis and click reaction of tubulin polymerization inhibitor 9-azido-α-noscapine
  作者：Naresh Kumar Manchukonda、Praveen Kumar Reddy Nagireddy、Balasubramanian Sridhar、Srinivas Kantevari

  DOI：10.1007/s11164-016-2773-7

  日期：2017.4

  Abstract An efficient protocol for the synthesis of tubulin polymerization inhibitor, 9-azido-α-noscapine 2h from 9-amino-α-noscapine 2g is developed using mild reaction conditions ( t -butyl nitrite/trimethylsilyl azide in acetonitrile at room temperature). Operational simplicity, high product yield without formation of any side products are the advantages of this protocol. Further copper catalyzed

  摘要 在温和的反应条件下（亚硝酸 叔 丁酯/叠氮化三甲基甲硅烷基叠氮化物在室温下），开发了一种由9-氨基-α-芥子 碱 2g 合成微管蛋白聚合抑制剂9-叠氮基-α-芥子碱 2h的有效方法 。该协议的优点是操作简单，产品产率高而不形成任何副产品。进一步的铜催化的9-叠氮基-α-芥子碱 2h 与炔烃 6a-f的 点击反应 产生了9-三唑基类胡萝卜素 7a-f， 产生了优异的收率。图形概要 开发了在温和的反应条件下由9-氨基-α-芥子碱合成9-叠氮基-α-芥子碱的友好协议；使用点击化学将其进一步衍生为三唑。
• Novel third-generation water-soluble noscapine analogs as superior microtubule-interfering agents with enhanced antiproliferative activity
  作者：Maged Henary、Lakshminarayana Narayana、Shazia Ahad、Sushma R. Gundala、Rao Mukkavilli、Vibhuti Sharma、Eric A. Owens、Yogesh Yadav、Mulpuri Nagaraju、Donald Hamelberg、Vibha Tandon、Dulal Panda、Ritu Aneja

  DOI：10.1016/j.bcp.2014.07.020

  日期：2014.11

  Noscapine, an opium-derived 'kinder-gentler' microtubule-modulating drug is in Phase I/II clinical trials for cancer chemotherapy. However, its limited water solubility encumbers its development into an oral anticancer drug with clinical promise. Here we report the synthesis of 9 third-generation, water-soluble noscapine analogs with negatively charged sulfonato and positively charged quaternary ammonium groups using noscapine, 9-bromonoscapine and 9-aminonoscapine as scaffolds. The predictive free energy of solvation was found to be lower for sulfonates (6a-c; 8a-c) compared to the quaternary ammonium-substituted counterparts, explaining their higher water solubility. In addition, sulfonates showed higher charge dispersability, which may effectively shield the hydrophobicity of isoquinoline nucleus as indicated by hydrophobicity mapping methods. These in silico data underscore efficient net charge balancing, which may explain higher water solubility and thus enhanced antiproliferative efficacy and improved bioavailability. We observed that 6b, 8b and Sc strongly inhibited tubulin polymerization and demonstrated significant antiproliferative activity against four cancer cell lines compared to noscapine. Molecular simulation and docking studies of tubulin-drug complexes revealed that the brominated compound with a four-carbon chain (4b, 6b, and 8b) showed optimal binding with tubulin heterodimers. Interestingly, 6b, 8b and Sc treated PC-3 cells resulted in preponderance of mitotic cells with multipolar spindle morphology, suggesting that they stall the cell cycle. Furthermore, in vivo pharmacokinetic evaluation of 6b, 8b and Sc revealed at least 1-2-fold improvement in their bioavailability compared to noscapine. To our knowledge, this is the first report to demonstrate novel water-soluble noscapine analogs that may pave the way for future pre-clinical drug development. (C) 2014 Elsevier Inc. All rights reserved.
• Combination of docetaxel and newly synthesized 9-Br-trimethoxybenzyl-noscapine improve tubulin binding and enhances antitumor activity in breast cancer cells
  作者：Shruti Gamya Dash、Srinivas Kantevari、Santosh Kumar Guru、Pradeep Kumar Naik

  DOI：10.1016/j.compbiomed.2021.104996

  日期：2021.12