9-Nitro-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-Nitro-Noscapine
• 英文别名: 9-nitro-α-noscapine；(S)-6,7-dimethoxy-3-((R)-4-methoxy-6-methyl-9-nitro-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)isobenzofuran-1(3H)-one；(3S)-6,7-dimethoxy-3-[(5R)-4-methoxy-6-methyl-9-nitro-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-5-yl]-3H-2-benzofuran-1-one
• 化学式: C₂₂H₂₂N₂O₉
• 分子量: 458.425
• InChiKey: MSOSTXVRGMHBBF-SJORKVTESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  33
• 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：
  122
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  9-Nitro-Noscapine 在 palladium on activated charcoal 、 氢气 作用下， 以83%的产率得到9-aminonoscapine
  参考文献：
  名称：

  Copper(I) mediated facile synthesis of potent tubulin polymerization inhibitor, 9-amino-α-noscapine from natural α-noscapine

  摘要：

  Facile synthesis of natural alpha-noscapine analogue, 9-amino-alpha-noscapine, a potent inhibitor of tubulin polymerization for cancer therapy, is achieved via copper(I) iodide mediated in situ aromatic azidation and reduction of 9-bromo-alpha-noscapine (obtained by bromination of natural alpha-noscapine) with NaN3 in DMSO at 130 degrees C in the presence of L-proline as an amino acid promoter. The protocol developed here avoided isolation of 9-azido-alpha-noscapine and did not cleave the sensitive C-C bond between two heterocyclic phthalide and isoquinoline units. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.02.033
• 作为产物：
  描述：

  那可汀 在 silver nitrate 、 三氟乙酸酐 作用下， 以 乙腈 为溶剂， 反应 1.0h， 生成 9-Nitro-Noscapine
  参考文献：
  名称：

  Development of a Novel Nitro-Derivative of Noscapine for the Potential Treatment of Drug-Resistant Ovarian Cancer and T-Cell Lymphoma

  摘要：

  我们之前已经表明，一种镇咳植物生物碱，那可丁，能够结合微管蛋白，表现出抗癌活性，并且在人类中具有安全的药理学特性。结构-功能分析指向异喹啉环上第9位的质子，可以在不影响微管蛋白结合活性的情况下进行修饰。因此，合成了许多在第9位具有不同功能基团的那可丁类似物。筛选出了那些能够杀死对其他抗微管蛋白药物（长春碱和紫杉醇）耐药的人类癌细胞的类似物。在这里，我们介绍其中一种类似物，9-硝基那可丁（9-硝基-NOS），它能够结合微管蛋白，并选择性地诱导对紫杉醇、长春碱和替尼泊苷耐药的肿瘤细胞（卵巢癌和T细胞淋巴瘤）的凋亡。9-硝基那可丁在高至100 μM的剂量下处理，不会影响正常人类成纤维细胞的细胞周期分布。这种对癌细胞的选择性使9-硝基那可丁在与现有抗有丝分裂药物相比中具有独特的优势。9-硝基那可丁通过有丝分裂停滞扰乱细胞周期进程，随后伴随着胱天蛋白酶-3激活增加和端粒酶末端脱氧核苷酸转移酶dUTP缺口末端标记阳性细胞的出现，导致凋亡性细胞死亡。因此，我们得出结论，9-硝基那可丁有很大的潜力成为一种新型治疗药物，用于治疗卵巢癌和T细胞淋巴瘤，即使是那些对目前可用化疗药物产生耐药性的癌症。

  DOI：

  10.1124/mol.105.021899

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。
• CONJUGATES OF NOSCAPINE AND FOLIC ACID AND THEIR USE IN TREATING CANCER
  申请人：Joshi Harish C.

  公开号：US20110286919A1

  公开（公告）日：2011-11-24

  The present invention is directed to compounds which are conjugates of two non-toxic natural products, noscapine (and various noscapine analogs) and folic acid (and various folic acid analogs), where the folic acid is conjugated to noscapine or the noscapine analog at the 9-position on the isoquinoline ring on the noscapine framework. Pharmaceutical compositions including the compounds, and methods of treating various tumors using the compounds and compositions, are also disclosed. The conjugates are particularly useful for treating cancers which overexpress the Folate Receptor α (FRa) receptor.

  本发明涉及两种非毒性天然产物，诺斯卡平（及各种诺斯卡平类似物）和叶酸（及各种叶酸类似物）的结合物，其中叶酸与诺斯卡平或诺斯卡平类似物在诺斯卡平框架上的异喹啉环的9位结合。还公开了包括该化合物的制药组合物以及使用该化合物和组合物治疗各种肿瘤的方法。这些结合物特别适用于治疗过度表达叶酸受体α（FRa）受体的癌症。
• 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：——