4'-O-demethyl-4β-(3''-aminoanilino)-4-desoxypodophyllotoxin chloride | 127882-78-4

• 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-demethyl-4β-(3''-aminoanilino)-4-desoxypodophyllotoxin chloride
• 英文别名: (5S,5aS,8aR,9R)-5-(3-aminoanilino)-9-(4-hydroxy-3,5-dimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one;hydrochloride
• CAS: 127882-78-4
• 化学式: C₂₇H₂₆N₂O₇*ClH
• 分子量: 526.974
• InChiKey: SBEXFGRMKNEIHB-TUHIZALYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.23
• 重原子数：
  37
• 可旋转键数：
  5
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  122
• 氢给体数：
  4
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  4'-O-demethyl-4β-(3''-aminoanilino)-4-desoxypodophyllotoxin chloride 、 8-((benzyloxy)amino)-8-oxooctanoic acid 在 2-( 1H-7-azabenzotniazol-1-yl)-1,1,3,3-tetrarmethyluroniumhexafluorophosphate methanaminium 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 12.0h， 以73%的产率得到
  参考文献：
  名称：

  The discovery and optimization of novel dual inhibitors of topoisomerase ii and histone deacetylase

  摘要：

  A novel class of podophyllotoxin derivatives have been designed and synthesized based on the synergistic antitumor effects of topoisomerase II and histone deacetylase inhibitors. Their inhibitory activities towards histone deacetylases and Topo II and their cytotoxicities in cancer cell lines were evaluated. The aromatic capping group connection, linker length and zinc-binding group were systematically varied and preliminary conclusions regarding structure-activity relationships are discussed. Among all of the synthesized hybrid compounds, compound 24d showed the most potent HDAC inhibitory activity at a low nanomolar level and exhibited powerful antiproliferative activity towards HCT116 colon carcinoma cells at a low micromolar level. Further exploration of this series led to the discovery of potent dual inhibitor 32, which exhibited the strongest in vitro cytotoxic activity. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2013.09.023
• 作为产物：
  描述：

  4'-O-demethyl-4β-(3''-nitroanilino)-4-desoxypodophyllotoxin 在 palladium on activated charcoal 盐酸 、 氢气 作用下， 以 乙酸乙酯 为溶剂， 反应 3.0h， 以75%的产率得到4'-O-demethyl-4β-(3''-aminoanilino)-4-desoxypodophyllotoxin chloride
  参考文献：
  名称：

  Antitumor agents. 113. New 4.beta.-arylamino derivatives of 4'-O-demethylepipodophyllotoxin and related compounds as potent inhibitors of human DNA topoisomerase II

  摘要：

  A number of 4'-O-demethylepipodophyllotoxin derivatives possessing various 4 beta-N-, 4 beta-O- or 4 beta-S-aromatic rings have been synthesized and evaluated for their inhibitory activity against the human DNA topoisomerase II as well as for their activity in causing cellular protein-linked DNA breakage. The results indicated, that for DNA topoisomerase II, a basic unsubstituted 4 beta-anilino moiety is structurally required for the enhanced activity. Substitution on this moiety with CN, COOCH3, COOC2H5, OH and COOCH3, OCH3, COCH3, CH2OH, OCH2O, OCH2CH2O, phenoxy, morpholino, NO2, and NH2 either at the para and/or the meta position yielded compounds which are as potent or more potent than etoposide. Substitution with COOC2H5 and OH at the ortho position afforded inactive compounds. Replacement of the aryl nitrogen with oxygen or sulfur gave compounds which are much less active or inactive. However, replacement of the phenyl ring with a pyridine nucleus furnished compounds which are as active or slightly more active than etoposide. There is a lack of correlation between the ability of these compounds in inhibiting DNA topoisomerase II and in causing protein-linked DNA breaks.

  DOI：

  10.1021/jm00171a050

文献信息

• WANG, ZHE-QING;KUO, YAO-HAUR;SCHNUR, DORA;BOWEN, J. PHILLIP;LIU, SU-YING;+, J. MED. CHEM., 33,(1990) N, C. 2660-2666
  作者：WANG, ZHE-QING、KUO, YAO-HAUR、SCHNUR, DORA、BOWEN, J. PHILLIP、LIU, SU-YING、+

  DOI：——

  日期：——
• Antitumor agents. 113. New 4.beta.-arylamino derivatives of 4'-O-demethylepipodophyllotoxin and related compounds as potent inhibitors of human DNA topoisomerase II
  作者：Zhe Qing Wang、Yao Haur Kuo、Dora Schnur、J. Phillip Bowen、Su Ying Liu、Fu Sheng Han、Jang Yang Chang、Yung Chi Cheng、Kuo Hsiung Lee

  DOI：10.1021/jm00171a050

  日期：1990.9

  A number of 4'-O-demethylepipodophyllotoxin derivatives possessing various 4 beta-N-, 4 beta-O- or 4 beta-S-aromatic rings have been synthesized and evaluated for their inhibitory activity against the human DNA topoisomerase II as well as for their activity in causing cellular protein-linked DNA breakage. The results indicated, that for DNA topoisomerase II, a basic unsubstituted 4 beta-anilino moiety is structurally required for the enhanced activity. Substitution on this moiety with CN, COOCH3, COOC2H5, OH and COOCH3, OCH3, COCH3, CH2OH, OCH2O, OCH2CH2O, phenoxy, morpholino, NO2, and NH2 either at the para and/or the meta position yielded compounds which are as potent or more potent than etoposide. Substitution with COOC2H5 and OH at the ortho position afforded inactive compounds. Replacement of the aryl nitrogen with oxygen or sulfur gave compounds which are much less active or inactive. However, replacement of the phenyl ring with a pyridine nucleus furnished compounds which are as active or slightly more active than etoposide. There is a lack of correlation between the ability of these compounds in inhibiting DNA topoisomerase II and in causing protein-linked DNA breaks.
• The discovery and optimization of novel dual inhibitors of topoisomerase ii and histone deacetylase
  作者：Xuan Zhang、Bin Bao、Xiuhua Yu、Linjiang Tong、Yu Luo、Qingqing Huang、Mingbo Su、Li Sheng、Jia Li、Hong Zhu、Bo Yang、Xiongwen Zhang、Yi Chen、Wei Lu

  DOI：10.1016/j.bmc.2013.09.023

  日期：2013.11

  A novel class of podophyllotoxin derivatives have been designed and synthesized based on the synergistic antitumor effects of topoisomerase II and histone deacetylase inhibitors. Their inhibitory activities towards histone deacetylases and Topo II and their cytotoxicities in cancer cell lines were evaluated. The aromatic capping group connection, linker length and zinc-binding group were systematically varied and preliminary conclusions regarding structure-activity relationships are discussed. Among all of the synthesized hybrid compounds, compound 24d showed the most potent HDAC inhibitory activity at a low nanomolar level and exhibited powerful antiproliferative activity towards HCT116 colon carcinoma cells at a low micromolar level. Further exploration of this series led to the discovery of potent dual inhibitor 32, which exhibited the strongest in vitro cytotoxic activity. (C) 2013 Elsevier Ltd. All rights reserved.