9-Fluoro-Noscapine

• 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: 9-Fluoro-Noscapine
• 英文别名: (S)-3-((R)-9-fluoro-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxyisobenzofuran-1(3H)-one；(s)-3-((r)-9-Fluoro-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxy-isobenzofuran-1(3h)-one；(3S)-3-[(5R)-9-fluoro-4-methoxy-6-methyl-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-5-yl]-6,7-dimethoxy-3H-2-benzofuran-1-one
• 化学式: C₂₂H₂₂FNO₇
• 分子量: 431.418
• InChiKey: BWXJGLKXCKGGKH-SJORKVTESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  75.7
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  那可汀 在 Amberlyst-A 26 、 溴 作用下， 以 四氢呋喃 、 氢溴酸 为溶剂， 反应 13.0h， 生成 9-Fluoro-Noscapine
  参考文献：
  名称：

  Synthesis of microtubule-interfering halogenated noscapine analogs that perturb mitosis in cancer cells followed by cell death

  摘要：

  We have previously identified the naturally occurring non-toxic antitussive phthalideiso-quinoline alkaloid, noscapine as a tubulin-binding agent that arrests mitosis and induces apoptosis. Here we present high-yield efficient synthetic methods and an evaluation of anticancer activity of halogenated noscapine analogs. our results show that all analogs display higher tubulin-binding activity than noscapine and inhibit proliferation of human cancer cells (MCF-7, MDA-MB-231 and CEM). Surprisingly, the bromo-analog is similar to 40-fold more potent than noscapine in inhibiting cellular proliferation of MCF-7 cells. The ability of these analogs to inhibit cellular proliferation is mediated by cell cycle arrest at the G(2)/M phase, in that all analogs except 9-iodonoscapine, caused selective mitotic arrest with a higher efficiency than noscapine followed by apoptotic cell death as shown by immunofluorescence and quantitative FACS analyses. Furthermore, our results reveal the appearance of numerous fragmented nuclei as evidenced by DAPI staining. Thus, our data indicate a great potential of these compounds for studying microtubule-mediated processes and as chemotherapeutic agents for the management of human cancers. (c) 2006 Elsevier Inc. All rights reserved.

  DOI：

  10.1016/j.bcp.2006.05.004

文献信息

• 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。
• NOSCAPINE ANALOGS AND THEIR USE IN TREATING CANCERS, INCLUDING DRUG-RESISTANT CANCERS
  申请人：Joshi Harish C.

  公开号：US20100227878A1

  公开（公告）日：2010-09-09

  Compounds, pharmaceutical compositions including the compounds, and methods of preparation and use thereof are disclosed. The compounds are noscapine analogs. The compounds and compositions can be used to treat and/or prevent a wide variety of cancers, including drug resistant cancers. While the antitussive plant alkaloid, noscapine, binds tubulin, displays anticancer activity, and has a safe pharmacological profile in humans, structure-function analyses pointed to a proton at position 9 of the isoquinoline ring that can be modified without compromising tubulin binding activity. Noscapine analogs with various functional moieties at position 9 on the isoquinoline ring kill human cancer cells resistant to other anti-microtubule agents, such as vincas and taxanes. Representative analogs include the 9-nitro, 9-bromo-, 9-iodo-, and 9-fluoro-noscapines, which bind tubulin and induce apoptosis selectively in tumor cells (ovarian and T-cell lymphoma) resistant to paclitaxel, vinblastine and teniposide. Surprisingly, treatment with one of the analogs, 9-nitro-nos, at doses as high as 100 μM, did not affect the cell cycle profile of normal human fibroblasts. This selectivity for cancer cells represents a unique edge over the other available antimitotics. The compounds can perturb the progression of cell cycle by mitotic arrest, followed by apoptotic cell death associated with increased caspase-3 activation and appearance of TUNEL-positive cells. Thus, the compounds are novel therapeutic agents for a variety of cancers, including ovarian and T-cell lymphoma cancers, even those that have become drug-resistant to currently available chemotherapeutic drugs.

  本文介绍了一种名为“Noscapine analogs”的化合物，以及包含这些化合物的制药组合物和制备和使用这些化合物的方法。这些化合物可用于治疗和/或预防各种癌症，包括耐药性癌症。虽然止咳植物生物碱Noscapine能够结合微管蛋白，显示出抗癌活性，并且在人类中具有安全的药理学特性，但结构-功能分析指出，异喹啉环上第9位的质子可以被修改而不影响微管蛋白结合活性。在异喹啉环上的第9位具有各种功能基团的Noscapine类似物能够杀死对其他抗微管蛋白剂（如维卡和紫杉醇）具有耐药性的人类癌细胞。代表性的类似物包括9-硝基、9-溴、9-碘和9-氟Noscapines，它们能够结合微管蛋白，并选择性地诱导卵巢和T细胞淋巴瘤等对紫杉醇、长春新和替尼泊苷具有耐药性的肿瘤细胞凋亡。令人惊讶的是，使用其中一种类似物9-硝基Nos在高达100μM的剂量下，不会影响正常人类成纤维细胞的细胞周期。这种对癌细胞的选择性代表着与其他可用的抗有丝分裂剂相比的独特优势。这些化合物可以通过有丝分裂阻滞干扰细胞周期的进程，随后通过增加Caspase-3的活化和TUNEL阳性细胞的出现引起凋亡性细胞死亡。因此，这些化合物是一种新的治疗剂，可用于治疗各种癌症，包括对目前可用的化疗药物具有耐药性的卵巢和T细胞淋巴瘤癌。
• NOSCAPINE ANALOGS AND THEIR USE IN TREATING CANCERS
  申请人：Joshi Harish C.

  公开号：US20130224310A1

  公开（公告）日：2013-08-29

  Compounds, pharmaceutical compositions including the compounds, and methods of preparation and use thereof are disclosed. The compounds are noscapine analogs. The compounds and compositions can be used to treat and/or prevent a wide variety of cancers, including drug resistant cancers. While the antitussive plant alkaloid, noscapine, binds tubulin, displays anticancer activity, and has a safe pharmacological profile in humans, structure-function analyses pointed to a proton at position 9 of the isoquinoline ring that can be modified without compromising tubulin binding activity. Noscapine analogs with various functional moieties at position 9 on the isoquinoline ring kill human cancer cells resistant to other anti-microtubule agents, such as vincas and taxanes.

  本文揭示了化合物、包括化合物的制药组合物以及其制备和使用方法。这些化合物是诺斯卡平类似物。这些化合物和组合物可用于治疗和/或预防各种癌症，包括耐药性癌症。虽然镇咳植物生物碱诺斯卡平能够结合微管蛋白，表现出抗癌活性，并且在人体中具有安全的药理特性，但结构-功能分析指出，异喹啉环上第9位的质子可以进行修饰而不影响微管蛋白的结合活性。在异喹啉环上第9位具有不同功能基团的诺斯卡平类似物可以杀死对其他抗微管蛋白剂（如维卡和紫杉醇）耐药的人类癌细胞。
• WO2008/109609
  申请人：——

  公开号：——

  公开（公告）日：——
• US8889705B2
  申请人：——

  公开号：US8889705B2

  公开（公告）日：2014-11-18