9-azido-α-noscapine | 1214255-24-9

• 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-azido-α-noscapine
• 英文别名: (S)-3-((R)-9-azido-4-methoxy-6-methyl-5,6,7,8-tetrahydro-[1,3]dioxolo[4,5-g]isoquinolin-5-yl)-6,7-dimethoxyisobenzofuran-1(3H)-one；9-azido-noscapine；(3S)-3-[(5R)-9-azido-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
• CAS: 1214255-24-9
• 化学式: C₂₂H₂₂N₄O₇
• 分子量: 454.439
• InChiKey: YTPMUGMKXIPOOF-SJORKVTESA-N

物化性质

• 熔点：
  116 °C

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  90
• 氢给体数：
  0
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  9-azido-α-noscapine 在 苯硫酚 、 三乙胺 、 tin(ll) chloride 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 以83%的产率得到9-aminonoscapine
  参考文献：
  名称：

  氨基诺斯卡品的合理设计、合成和生物学评价：一种高亲和力的微管蛋白结合诺斯卡素。

  摘要：

  Noscapine 及其衍生物是重要的微管干扰剂，具有强大的抗肿瘤活性。使用线性相互作用能 (LIE) 方法和表面广义玻恩 (SGB) 连续溶剂化模型计算的 noscapinoids 的结合自由能 (ΔG (bind)) 与实验 ΔG (bind) 一致，平均均方根误差为 0.082千卡/摩尔。这个 LIE-SGB 模型指导我们设计了一种新型的那可丁衍生物，氨基-那可丁 [(S)-3-((R)-9-amino-4-methoxy-6-methyl-5,6,7,8-四氢 [1, 3] 二氧戊环 [4,5-g]isoquinolin-5-yl)-6,7-二甲氧基异苯并呋喃-1(3H)-one] 具有更高的微管蛋白结合活性（预测的 ΔG (bind) = -6.438 kcal/mol 和实验 ΔG (bind) = -6.628 kcal/mol) 比那可品高，但不会显着改变微管蛋白亚基/聚合

  DOI：

  10.1007/s10822-011-9430-4
• 作为产物：
  描述：

  那可汀 在 copper(l) iodide 、 sodium azide 、 亚硝酸特丁酯 、 叠氮基三甲基硅烷 、 氢溴酸 、 溴 、 N,N'-二甲基乙二胺 作用下， 以 乙醇 、 水 、 乙腈 为溶剂， 反应 44.0h， 生成 9-azido-α-noscapine
  参考文献：
  名称：

  微管蛋白阻聚剂9-叠氮基-α-诺斯卡汀的合成及点击反应

  摘要：

  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。

  DOI：

  10.1007/s11164-016-2773-7

文献信息

• In silico inspired design and synthesis of a novel tubulin-binding anti-cancer drug: folate conjugated noscapine (Targetin)
  作者：Pradeep K. Naik、Manu Lopus、Ritu Aneja、Surya N. Vangapandu、Harish C. Joshi

  DOI：10.1007/s10822-011-9508-z

  日期：2012.2

  for cellular folate receptor alpha (FRα). FRα is over-expressed on some solid tumours such as ovarian epithelial cancers. Molecular docking experiments predicted that a folate conjugated noscapine (Targetin) accommodated well inside the binding cavity (docking score -11.295 kcal/mol) at the interface between α- and β-tubulin. The bulky folate moiety of Targetin is extended toward lumen of microtubules

  我们筛选不会解聚大量细胞微管的微管蛋白结合小分子，但基于众所周知的微管解聚秋水仙碱和鬼臼毒素的结构特征，揭示了那可碱的微管蛋白结合抗癌特性（Ye 等人在 Proc Natl Acad Sci美国 95:2280-2286, 1998)。在分子建模计算和构效关系的指导下，我们在诺斯卡品的 C9 处结合，叶酸基团 - 细胞叶酸受体 α (FRα) 的配体。FRα 在一些实体瘤如卵巢上皮癌中过度表达。分子对接实验预测，结合叶酸的那可品 (Targetin) 在 α- 和 β- 微管蛋白之间的界面处很好地容纳在结合腔内（对接分数 -11.295 kcal/mol）。Targetin 庞大的叶酸部分向微管腔延伸。基于分子力学能量最小化计算的结合自由能 (ΔG (bind)) 为 -221.01 kcal/mol，表明 Targetin 与受体之间存在良好的相互作用。化学合成、微管蛋白结合实验和体外抗
• 9-AMINONOSCAPINE AND ITS USE IN TREATING CANCERS, INCLUDING DRUG-RESISTANT CANCERS
  申请人：Joshi Harish C.

  公开号：US20110294844A1

  公开（公告）日：2011-12-01

  9-aminonoscapine, prodrugs thereof, and pharmaceutically acceptable salts thereof, are disclosed. Pharmaceutical compositions including 9-aminonoscapine, and methods of preparation and use thereof are disclosed. 9-aminonoscapine is a noscapine analog that can be used to treat and/or prevent a wide variety of cancers, including drug resistant cancers, by binding tubulin and inducing apoptosis selectively in tumor cells (ovarian and T-cell lymphoma) resistant to paclitaxel, vinblastine and teniposide. 9-aminonoscapine 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, 9-aminonoscapine is a 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.

  9-氨基诺斯卡平，其前药物以及其药用盐已被披露。包括9-氨基诺斯卡平的药物组合物，以及其制备和使用方法也已被披露。9-氨基诺斯卡平是一种诺斯卡平类似物，可用于治疗和/或预防各种癌症，包括对紫杉醇、长春新碱和替尼泊苷耐药的癌细胞（卵巢和T细胞淋巴瘤），通过结合微管蛋白并选择性诱导肿瘤细胞凋亡。9-氨基诺斯卡平可以通过有丝分裂阻滞扰乱细胞周期的进展，随后伴随着增加的caspase-3激活和TUNEL阳性细胞的出现而导致细胞凋亡。因此，9-氨基诺斯卡平是一种新型的治疗剂，可用于治疗各种癌症，包括卵巢和T细胞淋巴瘤癌，甚至那些已对当前可用的化疗药物产生耐药性的癌症。
• 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。
• 9-aminonoscapine and its use in treating cancers, including drug-resistant cancers
  申请人：Joshi Harish C.

  公开号：US08394957B2

  公开（公告）日：2013-03-12

  9-aminonoscapine, prodrugs thereof, and pharmaceutically acceptable salts thereof, are disclosed. Pharmaceutical compositions including 9-aminonoscapine, and methods of preparation and use thereof are disclosed. 9-aminonoscapine is a noscapine analog that can be used to treat and/or prevent a wide variety of cancers, including drug resistant cancers, by binding tubulin and inducing apoptosis selectively in tumor cells (ovarian and T-cell lymphoma) resistant to paclitaxel, vinblastine and teniposide. 9-aminonoscapine 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, 9-aminonoscapine is a 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9-氨基诺斯卡平及其前药和药学上可接受的盐。还介绍了包括9-氨基诺斯卡平的制药组合物以及其制备和使用方法。9-氨基诺斯卡平是一种诺斯卡平类似物，可以通过结合微管蛋白并在对紫杉醇、长春新和依托泊苷等药物产生耐药性的肿瘤细胞（卵巢和T细胞淋巴瘤）中选择性诱导细胞凋亡来治疗和/或预防各种癌症。9-氨基诺斯卡平可以通过有丝分裂阻滞干扰细胞周期的进展，随后通过增加caspase-3活化和TUNEL阳性细胞的出现引起细胞凋亡。因此，9-氨基诺斯卡平是一种新型的治疗剂，可用于治疗各种癌症，包括卵巢和T细胞淋巴瘤癌，即使这些癌症已经对当前可用的化疗药物产生了耐药性。
• Copper(I) mediated facile synthesis of potent tubulin polymerization inhibitor, 9-amino-α-noscapine from natural α-noscapine
  作者：Naresh K. Manchukonda、Balasubramanian Sridhar、Pradeep K. Naik、Harish C. Joshi、Srinivas Kantevari

  DOI：10.1016/j.bmcl.2012.02.033

  日期：2012.4

  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.