4-O-(5-methylpyrazine-2-carboxylic)-4'-demethylepipodophyllotoxin | 1469342-25-3

• 分子结构分类: 有机化合物 - 木脂素、新木脂素和相关化合物 - 木脂素内酯
• 英文名称: 4-O-(5-methylpyrazine-2-carboxylic)-4'-demethylepipodophyllotoxin
• 英文别名: [(5S,5aR,8aR,9R)-9-(4-hydroxy-3,5-dimethoxyphenyl)-8-oxo-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-5-yl] 5-methylpyrazine-2-carboxylate
• CAS: 1469342-25-3
• 化学式: C₂₇H₂₄N₂O₉
• 分子量: 520.496
• InChiKey: XSPZJFIILURDGF-VZYCYIEDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  38
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  136
• 氢给体数：
  1
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  5-甲基吡嗪-2-羧酸 、 4'-去甲基表鬼臼毒素 在 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 24.0h， 生成 4-O-(5-methylpyrazine-2-carboxylic)-4'-demethylepipodophyllotoxin
  参考文献：
  名称：

  A rational design strategy of the novel topoisomerase II inhibitors for the synthesis of the 4-O-(2-pyrazinecarboxylic)-4′-demethylepipodophyllotoxin with antitumor activity by diminishing the relaxation reaction of topoisomerase II-DNA decatenation

  摘要：

  A rational design strategy of the novel podophyllum topoisomerase II (Topo II) inhibitors for the synthesis of the esterification and amidation substituted 4'-demethylepipodophyllotoxin (DMEP) derivates was developed in order to discover the potential antitumor prodrug. Firstly, according to the structure-activity relationship, drug combination principle and bioisosterism, the -COO- and the -NH- bond substituents at the 4 position of cycloparaffin would be a great modification direction to improve antitumor activity of 4'-demethylepipodophyllotoxin (DMEP). Secondly, from the prodrug principle view, the esterification and amidation at the C-4 position of DMEP would be two useful structure modifications for improve solubility. Thirdly, from the activity pocket in Topo II-DNA cleavage complex point of view, a series of heterocyclic with pharmacological activity were chosen as module for improving antitumor activity by binding with Topo II. Finally, nine novel esterification and amidation DMEP derivates were designed and synthesized for the potential Topo II inhibitors with the superior biological activity. All the novel compounds exhibited promising in vitro antitumor activity, especially 4-O-(2-pyrazinecarboxylic)-4'- demethylepipodophyllotoxin (compound 1). The antitumor activity of compound 1 against tumor cell line HeLa (i.e., the IC50 value of 0.60 +/- 0.20 mu M), A549 (i.e., the IC50 value of 3.83 +/- 0.08 mu M), HepG2 (i.e., the IC50 value of 1.21 +/- 0.05 mu M), and BGC-823 (i.e., the IC50 value of 4.15 +/- 1.13 mu M) was significantly improved by 66, 16, 12, and 6 times than that of the clinically important podophyllum anticancer drug etoposide (i.e., the IC50 values of 15.32 +/- 0.10, 59.38 +/- 0.77, 67.25 +/- 7.05, and 30.74 +/- 5.13 mu M), respectively. Compound 1 could arrest HeLa cell cycle G(2)/M and induce apoptosis by strongly diminishing the relaxation reaction of Topo II-DNA decatenation. The correctness of rational drug design was strictly demonstrated by the bioactivity test. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.03.048

文献信息

• A rational design strategy of the novel topoisomerase II inhibitors for the synthesis of the 4-O-(2-pyrazinecarboxylic)-4′-demethylepipodophyllotoxin with antitumor activity by diminishing the relaxation reaction of topoisomerase II-DNA decatenation
  作者：Wei Zhao、Lu Chen、Hong-Mei Li、Duan-Ji Wang、Dong-Sheng Li、Tao Chen、Zhan-Peng Yuan、Ya-Jie Tang

  DOI：10.1016/j.bmc.2014.03.048

  日期：2014.6

  A rational design strategy of the novel podophyllum topoisomerase II (Topo II) inhibitors for the synthesis of the esterification and amidation substituted 4'-demethylepipodophyllotoxin (DMEP) derivates was developed in order to discover the potential antitumor prodrug. Firstly, according to the structure-activity relationship, drug combination principle and bioisosterism, the -COO- and the -NH- bond substituents at the 4 position of cycloparaffin would be a great modification direction to improve antitumor activity of 4'-demethylepipodophyllotoxin (DMEP). Secondly, from the prodrug principle view, the esterification and amidation at the C-4 position of DMEP would be two useful structure modifications for improve solubility. Thirdly, from the activity pocket in Topo II-DNA cleavage complex point of view, a series of heterocyclic with pharmacological activity were chosen as module for improving antitumor activity by binding with Topo II. Finally, nine novel esterification and amidation DMEP derivates were designed and synthesized for the potential Topo II inhibitors with the superior biological activity. All the novel compounds exhibited promising in vitro antitumor activity, especially 4-O-(2-pyrazinecarboxylic)-4'- demethylepipodophyllotoxin (compound 1). The antitumor activity of compound 1 against tumor cell line HeLa (i.e., the IC50 value of 0.60 +/- 0.20 mu M), A549 (i.e., the IC50 value of 3.83 +/- 0.08 mu M), HepG2 (i.e., the IC50 value of 1.21 +/- 0.05 mu M), and BGC-823 (i.e., the IC50 value of 4.15 +/- 1.13 mu M) was significantly improved by 66, 16, 12, and 6 times than that of the clinically important podophyllum anticancer drug etoposide (i.e., the IC50 values of 15.32 +/- 0.10, 59.38 +/- 0.77, 67.25 +/- 7.05, and 30.74 +/- 5.13 mu M), respectively. Compound 1 could arrest HeLa cell cycle G(2)/M and induce apoptosis by strongly diminishing the relaxation reaction of Topo II-DNA decatenation. The correctness of rational drug design was strictly demonstrated by the bioactivity test. (C) 2014 Elsevier Ltd. All rights reserved.