ethyl 4-((5R)-5-((1S)-4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-9-yl)benzoate

• 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: ethyl 4-((5R)-5-((1S)-4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-9-yl)benzoate
• 英文别名: (S)-6,7-dimethoxy-3-((R)-4-methoxy-6-methyl-9-(4-vinylphenyl)-5,6,7,8-tetrahydro-[1,3]dioxolo [4,5-g]isoquinolin-5-yl)isobenzofuran-1(3H)-one；ethyl 4-[(5R)-5-[(1S)-4,5-dimethoxy-3-oxo-1H-2-benzofuran-1-yl]-4-methoxy-6-methyl-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-9-yl]benzoate
• 化学式: C₃₁H₃₁NO₉
• 分子量: 561.588
• InChiKey: HCTPQDSLDNLGCJ-RPBOFIJWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  41
• 可旋转键数：
  8
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  102
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为产物：
  描述：

  那可汀 在 四(三苯基膦)钯 、 氢溴酸 、 碳酸氢钠 作用下， 以 乙醇 、 水 、 甲苯 为溶剂， 反应 48.0h， 生成 ethyl 4-((5R)-5-((1S)-4,5-dimethoxy-3-oxo-1,3-dihydroisobenzofuran-1-yl)-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-9-yl)benzoate
  参考文献：
  名称：

  Synthesis and biological evaluation of novel biaryl type α-noscapine congeners

  摘要：

  Natural alpha-noscapine, a known antitussive drug, is also now known to possess weak anticancer efficacy with relatively safe toxicity profile. In this study, we report synthesis and evaluation of novel biaryl type alpha-noscapine congeners designed by adding aryl unit to the tetrahydroisoquinoline part of natural alpha-noscapine core. Palladium catalyzed Suzuki cross coupling of 9-bromo alpha-noscapine with aryl boronic acids was employed using mild and inexpensive reagents to attain desired noscapinoids 5a-g in excellent yields. Screening anti-proliferative activity for new noscapinoids 5b-g, on human cancer cell lines resulted three compounds 5b, 5d and 5f as potent analogues, active against human breast epithelial (MCF-7), human cervix cancer (HeLa) and human lung adenocarcinoma epithelial (A549) cell lines. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2014.10.046

文献信息

• Rational design of biaryl pharmacophore inserted noscapine derivatives as potent tubulin binding anticancer agents
  作者：Seneha Santoshi、Naresh Kumar Manchukonda、Charu Suri、Manya Sharma、Balasubramanian Sridhar、Silja Joseph、Manu Lopus、Srinivas Kantevari、Iswar Baitharu、Pradeep Kumar Naik

  DOI：10.1007/s10822-014-9820-5

  日期：2015.3

  We have strategically designed a series of noscapine derivatives by inserting biaryl pharmacophore (a major structural constituent of many of the microtubule-targeting natural anticancer compounds) onto the scaffold structure of noscapine. Molecular interaction of these derivatives with α,β-tubulin heterodimer was investigated by molecular docking, molecular dynamics simulation, and binding free energy calculation. The predictive binding affinity indicates that the newly designed noscapinoids bind to tubulin with a greater affinity. The predictive binding free energy (ΔGbind, pred) of these derivatives (ranging from −5.568 to −5.970 kcal/mol) based on linear interaction energy (LIE) method with a surface generalized Born (SGB) continuum solvation model showed improved binding affinity with tubulin compared to the lead compound, natural α-noscapine (−5.505 kcal/mol). Guided by the computational findings, these new biaryl type α-noscapine congeners were synthesized from 9-bromo-α-noscapine using optimized Suzuki reaction conditions for further experimental evaluation. The derivatives showed improved inhibition of the proliferation of human breast cancer cells (MCF-7), human cervical cancer cells (HeLa) and human lung adenocarcinoma cells (A549), compared to natural noscapine. The cell cycle analysis in MCF-7 further revealed that these compounds alter the cell cycle profile and cause mitotic arrest at G2/M phase more strongly than noscapine. Tubulin binding assay revealed higher binding affinity to tubulin, as suggested by dissociation constant (Kd) of 126 ± 5.0 µM for 5a, 107 ± 5.0 µM for 5c, 70 ± 4.0 µM for 5d, and 68 ± 6.0 µM for 5e compared to noscapine (Kd of 152 ± 1.0 µM). In fact, the experimentally determined value of ΔGbind, expt (calculated from the Kd value) are consistent with the predicted value of ΔGbind, pred calculated based on LIE–SGB. Based on these results, one of the derivative 5e of this series was used for further toxicological evaluation. Treatment of mice with a daily dose of 300 mg/kg and a single dose of 600 mg/kg indicates that the compound does not induce detectable pathological abnormalities in normal tissues. Also there were no significant differences in hematological parameters between the treated and untreated groups. Hence, the newly designed noscapinoid, 5e is an orally bioavailable, safe and effective anticancer agent with a potential for the treatment of cancer and might be a candidate for clinical evaluation.

  我们通过将双芳基药性体（许多微管靶向天然抗癌化合物的主要结构成分）插入诺卡平的支架结构，战略性地设计了一系列诺卡平衍生物。通过分子对接、分子动力学模拟和结合自由能计算，研究了这些衍生物与α、β-微管蛋白异源二聚体的分子相互作用。预测的结合亲和力表明，新设计的 noscapinoids 能以更大的亲和力与微管蛋白结合。这些衍生物的预测结合自由能（ΔGbind，pred）（从-5.568到-5.970 kcal/mol）基于线性相互作用能（LIE）方法和表面广义博恩（SGB）连续溶解模型，与先导化合物天然α-莨菪碱（-5.505 kcal/mol）相比，与小管蛋白的结合亲和力有所提高。在计算结果的指导下，我们采用优化的铃木反应条件，从 9-溴-α-莨菪碱合成了这些新的双芳基型 α-莨菪碱同系物，并进行了进一步的实验评估。与天然莨菪碱相比，这些衍生物对人类乳腺癌细胞（MCF-7）、人类宫颈癌细胞（HeLa）和人类肺腺癌细胞（A549）增殖的抑制效果更好。在 MCF-7 细胞中进行的细胞周期分析进一步显示，这些化合物改变了细胞周期轮廓，并比诺卡品更强烈地导致有丝分裂停滞在 G2/M 期。5a的解离常数（Kd）为126 ± 5.0 µM，5a的解离常数（Kd）为107 ± 5.0 µM。0 µM，5d 为 70 ± 4.0 µM ，5e 为 68 ± 6.0 µM ，而诺卡平（Kd 为 152 ± 1.0 µM）。事实上，实验测定的 ΔGbind, expt 值（根据 Kd 值计算得出）与根据 LIE-SGB 计算得出的 ΔGbind, pred 预测值一致。基于这些结果，该系列中的一种衍生物 5e 被用于进一步的毒理学评估。对小鼠进行每日剂量为 300 mg/kg 和单次剂量为 600 mg/kg 的处理表明，该化合物不会在正常组织中诱发可检测到的病理异常。此外，治疗组和未治疗组之间的血液学参数也没有明显差异。因此，新设计的 5e 是一种口服生物利用度高、安全有效的抗癌剂，具有治疗癌症的潜力，可能成为临床评估的候选药物。
• Noscapine and Noscapine Analogs and Their Use in treating Infectious Diseases by Tubulin Binding Inhibition
  申请人：Acuff Cory

  公开号：US20110274651A1

  公开（公告）日：2011-11-10

  Compositions and methods for treating or preventing infectious diseases, and inhibiting the ability of microbes to travel within mammalian cells, and inhibiting microbial replication, are disclosed. The compositions include various noscapine analogs, which are capable of blocking the movement of viruses and other microbes within mammalian and other cells by inhibiting the cytoplasmic transport mechanisms within the cells. The compositions described herein include an effective amount of the noscapine analogues described herein, along with a pharmaceutically acceptable carrier or excipient. The compositions can also include one or more additional antimicrobial compounds.

  本发明公开了用于治疗或预防传染病、抑制微生物在哺乳动物细胞内移动和抑制微生物复制能力的组合物和方法。该组合物包括各种诺斯卡平类似物，能够通过抑制细胞内的胞质转运机制，阻止病毒和其他微生物在哺乳动物和其他细胞内移动。本发明所描述的组合物包括所述诺斯卡平类似物的有效量，以及药学上可接受的载体或赋形剂。该组合物还可以包括一个或多个额外的抗微生物化合物。
• Synthesis and biological evaluation of novel biaryl type α-noscapine congeners
  作者：Naresh K. Manchukonda、Pradeep K. Naik、Balasubramanian Sridhar、Srinivas Kantevari

  DOI：10.1016/j.bmcl.2014.10.046

  日期：2014.12

  Natural alpha-noscapine, a known antitussive drug, is also now known to possess weak anticancer efficacy with relatively safe toxicity profile. In this study, we report synthesis and evaluation of novel biaryl type alpha-noscapine congeners designed by adding aryl unit to the tetrahydroisoquinoline part of natural alpha-noscapine core. Palladium catalyzed Suzuki cross coupling of 9-bromo alpha-noscapine with aryl boronic acids was employed using mild and inexpensive reagents to attain desired noscapinoids 5a-g in excellent yields. Screening anti-proliferative activity for new noscapinoids 5b-g, on human cancer cell lines resulted three compounds 5b, 5d and 5f as potent analogues, active against human breast epithelial (MCF-7), human cervix cancer (HeLa) and human lung adenocarcinoma epithelial (A549) cell lines. (C) 2014 Elsevier Ltd. All rights reserved.