4'-demethylepipodophyllotoxin ethyl ether | 102306-95-6

• 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'-demethylepipodophyllotoxin ethyl ether
• 英文别名: 4'-demethyl-1-O-ethyl-1-epipodophyllotoxin；Deglucopyranosyl Ethoxy Etoposide；(5S,5aR,8aR,9R)-5-ethoxy-9-(4-hydroxy-3,5-dimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one
• CAS: 102306-95-6
• 化学式: C₂₃H₂₄O₈
• 分子量: 428.439
• InChiKey: XWWKNDVCCMQSIV-COWZOJLOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  31
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  92.7
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  在 palladium on activated charcoal 氢气 作用下， 以 甲醇 、 乙酸乙酯 为溶剂， 反应 3.0h， 生成 4'-demethylepipodophyllotoxin ethyl ether
  参考文献：
  名称：

  Antitumor Agents. I. DNA Topoisomerase II Inhibitory Activity and the Structural Relationship of Podophyllotoxin Derivatives as Antitumor Agents.

  摘要：

  合成了多种来自脱氧髓鞘素（DPT）的紫苑毒素衍生物，以研究其在体外的生物重要性（细胞毒性、对 DNA 拓扑异构酶 II 的影响和微管聚合影响）与在体内的抗肿瘤活性（L 1210）之间的结构关系。DPT 的完整 6, 7-亚甲基二氧基基团是抑制微管聚合和拓扑异构酶 II 所必需的。DPT 的 4'-酚羟基对于抑制 DNA 拓扑异构酶 II 是必不可少的，而对 DNA 拓扑异构酶 II 的抑制作用导致了高细胞毒性。DPT 在 1 位置引入氨基烷氧基团增强了对 DNA 拓扑异构酶 II 的抑制活性和细胞毒性，导致对微管聚合的抑制活性消失。在 L 1210 移植小鼠中对紫苑毒素衍生物的抗肿瘤测试结果表明：1）只要与抑制微管聚合相关，强细胞毒性本身并不是评估体内抗肿瘤活性的良好指征。DNA 拓扑异构酶 II 的抑制作用对体内抗肿瘤活性有贡献；2）为了评估紫苑毒素衍生物，需详细测定体外的细胞毒性及对 DNA 拓扑异构酶 II 和微管聚合的抑制作用。

  DOI：

  10.1248/cpb.40.2720

文献信息

• Antitumor agents. 100. Inhibition of human DNA topoisomerase II by cytotoxic ether and ester derivatives of podophyllotoxin and .alpha.-peltatin
  作者：Lee S. Thurston、Yasuhiro Imakura、Mitsumasa Haruna、De Hua Li、Zong Chao Liu、Su Ying Liu、Yung Chi Cheng、Kuo Hsiung Lee

  DOI：10.1021/jm00123a016

  日期：1989.3

  A principal mechanism of action of the clinical antitumor drugs etoposide (1) and teniposide (2) is the inhibition of catalytic activity of type II DNA topoisomerase and concurrent enzyme-mediated production of lethal DNA strand breaks. Substitution of the glycosidic moiety of 1 or 2 by ester and ethers, as well as the esterification and etherification of alpha-peltatin (4) including its glucosidic ethylidene and thenylidene cyclic acetals (25 and 26), has afforded compounds of much less activity than that of 1. The in vitro cytotoxicity (KB) appears to have no correlation with the inhibitory activity of the human DNA topoisomerase II.
• Antitumor agents. 78. Inhibition of human DNA topoisomerase II by podophyllotoxin and .alpha.-peltatin analogs
  作者：Lee S. Thurston、Hiroshi Irie、Shohei Tani、Fu Sheng Han、Zong Chao Liu、Yung Chi Cheng、Kuo Hsiung Lee

  DOI：10.1021/jm00158a042

  日期：1986.8

  It has been reported that the action of etoposide (VP-16) (14) as an antitumor agent is mediated through its interaction with DNA topoisomerase II which results in DNA breakage inside the cell. In order to understand the mechanism of action as well as structure-activity relationships of 14, several novel, synthetic and some naturally occurring analogues related to podophyllotoxin were examined for inhibition of the DNA topoisomerase II activity. Compound 2 exhibited enhanced activity and compound 5 slightly diminished activity relative to 14. A 4 beta-substituted ether at the C ring and O-demethylation at the E ring appear to enhance activity.
• THURSTON, LEE S.;IMAKURA, YASUHIRO;HARUNA, MITSUMASA;LI, DE-HUA;LIU, ZONG+, J. MED. CHEM., 32,(1989) N, C. 604-608
  作者：THURSTON, LEE S.、IMAKURA, YASUHIRO、HARUNA, MITSUMASA、LI, DE-HUA、LIU, ZONG+

  DOI：——

  日期：——
• Antitumor Agents. I. DNA Topoisomerase II Inhibitory Activity and the Structural Relationship of Podophyllotoxin Derivatives as Antitumor Agents.
  作者：Tadafumi TERADA、Katsuhiko FUJIMOTO、Makoto NOMURA、Jun-ichi YAMASHITA、Takashi KOBUNAI、Setsuo TAKEDA、Konstanty WIERZBA、Yuji YAMADA、Hideo YAMAGUCHI

  DOI：10.1248/cpb.40.2720

  日期：——

  Various podophyllotoxin derivatives from desoxypodophyllotoxin (DPT) were synthesized to examine the structural relationships between the biological significance (cytotoxic effect, effects on DNA topoisomerase II and tubulin polymerization) in vitro and antitumor activity in vivo (L 1210).An intact 6, 7-methylenedioxy group of DPT is necessary to inhibit tubulin polymerization and topoisomerase II. 4'-Phenolic hydroxyl group of DPT is essential to inhibit DNA topoisomerase II and the inhibitory effect on DNA topoisomerase II contributes to a high cytotoxicity.The introduction of an aminoalkoxy group at 1-position of DPT enhances the inhibitory activity against DNA topoisomerase II and cytotoxic effect, causing the inhibitory activity against tubulin polymerization to disappear. The results of antitumor test in mice bearing L 1210 on podophyllotoxin derivatives suggest the following : 1) the strong cytotoxic effect itself is not a good indication of antitumor activity in vivo as long as it is associated with inhibition of tubulin polymerization. DNA topoisomerase II inhibitory effect contributes to an antitumor activity in vivo; 2) detailed measurements of cytotoxicity and inhibition on DNA topoisomerase II and tubulin polymerization in vitro are necessary to evaluate podophyllotoxin derivatives.

  合成了多种来自脱氧髓鞘素（DPT）的紫苑毒素衍生物，以研究其在体外的生物重要性（细胞毒性、对 DNA 拓扑异构酶 II 的影响和微管聚合影响）与在体内的抗肿瘤活性（L 1210）之间的结构关系。DPT 的完整 6, 7-亚甲基二氧基基团是抑制微管聚合和拓扑异构酶 II 所必需的。DPT 的 4'-酚羟基对于抑制 DNA 拓扑异构酶 II 是必不可少的，而对 DNA 拓扑异构酶 II 的抑制作用导致了高细胞毒性。DPT 在 1 位置引入氨基烷氧基团增强了对 DNA 拓扑异构酶 II 的抑制活性和细胞毒性，导致对微管聚合的抑制活性消失。在 L 1210 移植小鼠中对紫苑毒素衍生物的抗肿瘤测试结果表明：1）只要与抑制微管聚合相关，强细胞毒性本身并不是评估体内抗肿瘤活性的良好指征。DNA 拓扑异构酶 II 的抑制作用对体内抗肿瘤活性有贡献；2）为了评估紫苑毒素衍生物，需详细测定体外的细胞毒性及对 DNA 拓扑异构酶 II 和微管聚合的抑制作用。