(6RS,11aSR)-6-hydroxymethyl-2-isopropyloxycarbonyl-7,8,10-trimethoxy-9-methyl-1,2,3,6,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-4-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 四氢异喹啉
• 英文名称: (6RS,11aSR)-6-hydroxymethyl-2-isopropyloxycarbonyl-7,8,10-trimethoxy-9-methyl-1,2,3,6,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-4-one
• 英文别名: propan-2-yl (6R,11aS)-6-(hydroxymethyl)-7,8,10-trimethoxy-9-methyl-4-oxo-3,6,11,11a-tetrahydro-1H-pyrazino[1,2-b]isoquinoline-2-carboxylate
• 化学式: C₂₁H₃₀N₂O₇
• 分子量: 422.478
• InChiKey: YTIYCENRHHAJBM-ZFWWWQNUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  30
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  97.8
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (6RS,11aSR)-6-hydroxymethyl-2-isopropyloxycarbonyl-7,8,10-trimethoxy-9-methyl-1,2,3,6,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-4-one 在 硫酸 、 三氟乙酸 作用下， 反应 16.0h， 以50%的产率得到(6RS,11aSR)-6-hydroxymethyl-7,8,10-trimethoxy-9-methyl-1,2,3,6,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-4-one
  参考文献：
  名称：

  Pyrazino[1,2-b]isoquinolines: Synthesis and study of their cytostatic and cytotoxic properties

  摘要：

  The in vitro antitumor potential of novel pyrazino[1,2-b]-isoquinoline-4-ones that contain a half portion of significant natural products was explored in three cancer cell lines: MDA-MB 231 human breast carcinoma, A-549 human lung carcinoma, and HT-29 human colon carcinoma. In general, these compounds show mid to low mu M GI(50)s, but LC(50)s over 100 mu M with the exceptions of compounds 3b and 31 that are moderately toxic in all cell lines, while compound 4a is highly toxic and selective for HT-29 cells with LC50 values in the high nanomolar range. Experiments directed to elucidate possible mechanisms of action with compounds 3a, 29, and 31 showed that compound 3a is able to efficiently induce apoptosis triggered directly from the G2/M phase of cell cycle, while compounds 29 and 31 are potentially cytostatic agents that induce the G1/S arrest of cell cycle. All three compounds do not act through DNA damage, since they do not activate this signaling at the level of sensors, transducers, and executers. Furthermore, the apoptosis induction of 3a is not mediated by activation of pro-apoptotic kinases JNK and p38 or by activation of AKT. (C) 2008 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2008.07.083
• 作为产物：
  描述：

  propan-2-yl (6R,11aS)-7,8,10-trimethoxy-9-methyl-4-oxo-6-(phenylmethoxymethyl)-3,6,11,11a-tetrahydro-1H-pyrazino[1,2-b]isoquinoline-2-carboxylate 在 palladium 10% on activated carbon 、 氢气 作用下， 以 乙醇 为溶剂， 反应 16.0h， 以98%的产率得到(6RS,11aSR)-6-hydroxymethyl-2-isopropyloxycarbonyl-7,8,10-trimethoxy-9-methyl-1,2,3,6,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-4-one
  参考文献：
  名称：

  吡嗪并[1,2 - b ]异喹啉-4-酮的细胞毒性机理与SAR研究

  摘要：

  通过显示细胞毒性1B，获得标题化合物的有趣representant，对于HT-29人结肠癌细胞（CI 50的1.95×10值-7  M）已经在G2期，而不是DNA已涉及到诱导的细胞死亡损害。该化合物促进G2 / M检查点机制的组件（尤其是cdc2，Cyclin B1和Wee1）的降解，这代表了一种新的细胞毒性机制。Wee1的降解似乎是由蛋白酶体活性介导的，但cdc2的降解必须通过不同的机制发生。1b对G2细胞周期成分的活性表明，化合物1b可以靶向被顺铂等抗癌药物阻滞在G2 / M中的肿瘤细胞，增加细胞凋亡的诱导作用，以及它们的优化类似物可通过与顺铂或其他影响细胞骨架完整性的抗癌药物（例如紫杉酚和紫杉醇）的联合疗法用于结肠癌的治疗。 SAR研究通过操纵N（2）和C（4）-官能团以及化合物1b的C（6）链获得的化合物已经证实了这些结构特征在体外抗肿瘤活性中的重要性。稠合的恶唑烷衍生物作为化合物

  DOI：

  10.1016/j.bmc.2009.10.007

文献信息

• Cytotoxicity mechanisms of pyrazino[1,2-b]isoquinoline-4-ones and SAR studies
  作者：Irene Ortín、Juan Francisco González、Elena de la Cuesta、Cristina Manguan-García、Rosario Perona、Carmen Avendaño

  DOI：10.1016/j.bmc.2009.10.007

  日期：2009.12

  analogs might be useful in the treatment of colon cancer through combination therapies with cisplatin or other anticancer drugs that affect the cytoskeleton integrity such as taxol and taxotere. SAR studies with compounds obtained by manipulation of the N(2) and C(4)-functional groups and the C(6)-chain of compound 1b have confirmed the importance of these structural features in the in vitro antitumor

  通过显示细胞毒性1B，获得标题化合物的有趣representant，对于HT-29人结肠癌细胞（CI 50的1.95×10值-7  M）已经在G2期，而不是DNA已涉及到诱导的细胞死亡损害。该化合物促进G2 / M检查点机制的组件（尤其是cdc2，Cyclin B1和Wee1）的降解，这代表了一种新的细胞毒性机制。Wee1的降解似乎是由蛋白酶体活性介导的，但cdc2的降解必须通过不同的机制发生。1b对G2细胞周期成分的活性表明，化合物1b可以靶向被顺铂等抗癌药物阻滞在G2 / M中的肿瘤细胞，增加细胞凋亡的诱导作用，以及它们的优化类似物可通过与顺铂或其他影响细胞骨架完整性的抗癌药物（例如紫杉酚和紫杉醇）的联合疗法用于结肠癌的治疗。 SAR研究通过操纵N（2）和C（4）-官能团以及化合物1b的C（6）链获得的化合物已经证实了这些结构特征在体外抗肿瘤活性中的重要性。稠合的恶唑烷衍生物作为化合物
• Pyrazino[1,2-b]isoquinolines: Synthesis and study of their cytostatic and cytotoxic properties
  作者：Irene Ortín、Juan Francisco González、Elena de la Cuesta、Cristina Manguan-García、Rosario Perona、Carmen Avendaño

  DOI：10.1016/j.bmc.2008.07.083

  日期：2008.10

  The in vitro antitumor potential of novel pyrazino[1,2-b]-isoquinoline-4-ones that contain a half portion of significant natural products was explored in three cancer cell lines: MDA-MB 231 human breast carcinoma, A-549 human lung carcinoma, and HT-29 human colon carcinoma. In general, these compounds show mid to low mu M GI(50)s, but LC(50)s over 100 mu M with the exceptions of compounds 3b and 31 that are moderately toxic in all cell lines, while compound 4a is highly toxic and selective for HT-29 cells with LC50 values in the high nanomolar range. Experiments directed to elucidate possible mechanisms of action with compounds 3a, 29, and 31 showed that compound 3a is able to efficiently induce apoptosis triggered directly from the G2/M phase of cell cycle, while compounds 29 and 31 are potentially cytostatic agents that induce the G1/S arrest of cell cycle. All three compounds do not act through DNA damage, since they do not activate this signaling at the level of sensors, transducers, and executers. Furthermore, the apoptosis induction of 3a is not mediated by activation of pro-apoptotic kinases JNK and p38 or by activation of AKT. (C) 2008 Elsevier Ltd. All rights reserved.