4'-(tert-butyldimethylsilyl)-4'-demethylepipodophyllotoxin | 118356-07-3

• 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'-(tert-butyldimethylsilyl)-4'-demethylepipodophyllotoxin
• 英文别名: 4'-O-tert-butyldimethylsilanyl-4'-O-demethyl-4-epipodophyllotoxin；(5S,5aR,8aR,9R)-9-[4-[tert-butyl(dimethyl)silyl]oxy-3,5-dimethoxyphenyl]-5-hydroxy-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one
• CAS: 118356-07-3
• 化学式: C₂₇H₃₄O₈Si
• 分子量: 514.648
• InChiKey: VEWIRKVNHZJDKT-QQJYNPJZSA-N

物化性质

• 熔点：
  212 °C(Solv: methanol (67-56-1))
• 沸点：
  619.9±55.0 °C(Predicted)
• 密度：
  1.223±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.78
• 重原子数：
  36
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  92.7
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  4'-(tert-butyldimethylsilyl)-4'-demethylepipodophyllotoxin 在 4-二甲氨基吡啶 、 四丁基氟化铵 、 对甲苯磺酸 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 5.25h， 生成 α-peltatin 5-<4,6-O-(R)-ethylidene-β-D-glucopyranoside>
  参考文献：
  名称：

  Antitumor agents. 100. Inhibition of human DNA topoisomerase II by cytotoxic ether and ester derivatives of podophyllotoxin and .alpha.-peltatin

  摘要：

  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.

  DOI：

  10.1021/jm00123a016
• 作为产物：
  描述：

  鬼臼毒素 在 咪唑 、 水 、 氢溴酸 、 barium carbonate 作用下， 以 四氢呋喃 为溶剂， 反应 22.0h， 生成 4'-(tert-butyldimethylsilyl)-4'-demethylepipodophyllotoxin
  参考文献：
  名称：

  Antitumor agents. 100. Inhibition of human DNA topoisomerase II by cytotoxic ether and ester derivatives of podophyllotoxin and .alpha.-peltatin

  摘要：

  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.

  DOI：

  10.1021/jm00123a016

文献信息

• Synthesis of podophyllotoxin analogues: δ-lactone-containing picropodophyllin, podophyllotoxin and 4′-demethyl-epipodophyllotoxin derivatives
  作者：Philippe Meresse、Claude Monneret、Emmanuel Bertounesque

  DOI：10.1016/j.tet.2004.01.017

  日期：2004.3

  cyano group, led to the trans δ-lactone 5 (7 steps from 1 and 6% overall yied) with a small amount of its C-4 epimer 6. The synthesis of non-epimerizable δ-lactone analogues of 4′-demethyl-epipodophyllotoxin 7 and of 4-demethyl podophyllotoxin 8 are also reported. The synthesis of 7 and 8 was based upon the reduction of the γ-lactone ring of 4′-demethyl-4-epipodophyllotoxin followed by selective protection

  已经制备了鬼臼毒素的不可表位的顺式和反式δ-内酯类似物。因此，通过将γ内酯环还原成反式二醇，选择性保护4-OH和11-OH作为亚苄基乙缩醛，鬼臼毒素1的合成已经完成了8个步骤，并且鬼臼毒素1的总收率为4％，从而实现了顺式异构体4的合成。，以及Wittig在C-13处的延伸，以及C-2处的构型反转。在C-13处具有相同的伸长率，但通过形成甲磺酸酯和引入氰基基团，产生了带有少量C-4差向异构体的反式δ-内酯5（从1和6％的总收率起7步）6。还报道了4'-脱甲基-表鬼臼毒素7和4-脱甲基鬼臼毒素8的不可表位的δ-内酯类似物的合成。7和8的合成是基于还原4'-去甲基-4-表鬼臼毒素的γ-内酯环，然后在C-11处进行选择性保护，并在C-13处进行延伸。（总产量的8-15％和4％）。化合物4，5和7没有对L1210鼠白血病显示体外相关的细胞毒性。
• 两种依托泊苷杂质的制备方法
  申请人：梯尔希（南京）药物研发有限公司

  公开号：CN113121618A

  公开（公告）日：2021-07-16

  本发明公开了两种依托泊苷杂质的制备方法,本发明以硅醚保护的4'‑去甲基表鬼臼毒素为起始原料，使用光延反应与依托泊苷缩合、脱保护得到Etoposide EP Impurity R、再经过缩醛水解得到Etoposide Impurity 2。本发明整个路线设计合理，后处理简单、原料易得；制备得到的目标产物纯度可达99.5%以上，可用于药理以及毒理的研究，以及作为药品生产过程中的杂质控制的参考标准。
• Hemi-synthesis and Biological Activity of New Analogues of Podophyllotoxin
  作者：Emmanuel Roulland、Prokopios Magiatis、Paola Arimondo、Emmanuel Bertounesque、Claude Monneret

  DOI：10.1016/s0968-0896(02)00255-9

  日期：2002.11

  Various 4-analogues of podophyllotoxin and epipodophyllotoxin were obtained via the formation of the corresponding 4-keto derivatives. Methyloximation of podophyllotoxone, followed by subsequent catalytic hydrogenation, gave stereoselective access to 4-alpha-amino-4-deoxypodophyllotoxin and from there, to the corresponding acetamido and formamido derivatives. Base-catalyzed isomerisation of 4-alph

  鬼臼毒素和表鬼臼毒素的各种4-类似物是通过形成相应的4-酮衍生物获得的。鬼臼毒素的甲基肟化，随后进行催化氢化，使立体选择性地进入4-α-氨基-4-脱氧鬼臼毒素，并从那里立体定向地进入相应的乙酰氨基和甲酰胺基衍生物。碱催化的4-α-氨基-4-脱氧鬼臼毒素的异构化导致相应的鬼臼苦素异构体，而4-β-氨基则提供了新鬼臼毒素样的衍生物。另一方面，使用Takai烯化策略由鬼臼毒素和4-epi-4'-去甲基鬼臼毒素制备环氧乙烷和含羟甲基的类似物。在后一个系列中，还合成了含甲醛和羧酸的衍生物。
• 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. 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.