9'-methylnoscapine | 1374880-69-9

• 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'-methylnoscapine
• 英文别名: (3S)-6,7-dimethoxy-3-[(5R)-4-methoxy-6,9-dimethyl-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-5-yl]-3H-2-benzofuran-1-one
• CAS: 1374880-69-9
• 化学式: C₂₃H₂₅NO₇
• 分子量: 427.454
• InChiKey: UVSRVHUEWXARJU-MJGOQNOKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  75.7
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  甲基硼酸 、 9-bromonoscapine 在 potassium phosphate 、 palladium diacetate 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 以44%的产率得到9'-methylnoscapine
  参考文献：
  名称：

  Novel 9′-substituted-noscapines: Synthesis with Suzuki cross-coupling, structure elucidation and biological evaluation

  摘要：

  Tubulin is a major molecular target for anticancer drugs. The dynamic process of microtubule assembly and disassembly can be blocked by various agents that bind to distinct sites on tubulin, usually its β-subunit. Among the antimitotic agents that perturb microtubule dynamics, noscapinoids represent an emerging class of agents. In particular, 9'-bromonoscapine (EM011) has been identified as a potent noscapine analog. Here we present high yielding, efficient synthetic methods based on Suzuki coupling of 9'-alkyl and 9'-arylnoscapines and an evaluation of their antiproliferative properties. Our results showed that 9'-alkyl and 9'-aryl derivatives inhibit proliferation of human cancer cells. The most active compounds were the 9'-methyl and the 9'-phenyl derivatives, which showed similar cytotoxic potency in comparison to the 9'-brominated derivative. Interestingly these newly synthesized derivatives did not induce cell death in normal human lymphocytes, suggesting that the compounds may be selective against cancer cells. All of these derivatives, except 9'-(2-methoxyphenyl)-noscapine, efficiently induced a cell cycle arrest in the G2/M phase of the cell cycle in HeLa and Jurkat cells. Furthermore, we showed that the most active compounds in HeLa cells induced apoptosis following the mitochondrial pathway with the activation of both caspase-9 and caspase-3. In addition, these compounds significantly reduced the expression of the anti-apoptotic proteins Mcl-1 and Bcl-2.

  DOI：

  10.1016/j.ejmech.2014.07.050

文献信息

• 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。
• Novel 9′-substituted-noscapines: Synthesis with Suzuki cross-coupling, structure elucidation and biological evaluation
  作者：Elena Porcù、Attila Sipos、Giuseppe Basso、Ernest Hamel、Ruoli Bai、Verena Stempfer、Antal Udvardy、Attila Cs. Bényei、Helmut Schmidhammer、Sándor Antus、Giampietro Viola

  DOI：10.1016/j.ejmech.2014.07.050

  日期：2014.9

  Tubulin is a major molecular target for anticancer drugs. The dynamic process of microtubule assembly and disassembly can be blocked by various agents that bind to distinct sites on tubulin, usually its β-subunit. Among the antimitotic agents that perturb microtubule dynamics, noscapinoids represent an emerging class of agents. In particular, 9'-bromonoscapine (EM011) has been identified as a potent noscapine analog. Here we present high yielding, efficient synthetic methods based on Suzuki coupling of 9'-alkyl and 9'-arylnoscapines and an evaluation of their antiproliferative properties. Our results showed that 9'-alkyl and 9'-aryl derivatives inhibit proliferation of human cancer cells. The most active compounds were the 9'-methyl and the 9'-phenyl derivatives, which showed similar cytotoxic potency in comparison to the 9'-brominated derivative. Interestingly these newly synthesized derivatives did not induce cell death in normal human lymphocytes, suggesting that the compounds may be selective against cancer cells. All of these derivatives, except 9'-(2-methoxyphenyl)-noscapine, efficiently induced a cell cycle arrest in the G2/M phase of the cell cycle in HeLa and Jurkat cells. Furthermore, we showed that the most active compounds in HeLa cells induced apoptosis following the mitochondrial pathway with the activation of both caspase-9 and caspase-3. In addition, these compounds significantly reduced the expression of the anti-apoptotic proteins Mcl-1 and Bcl-2.