(5R,5aR,8aS,9S)-9-[(4-氨基苯基)氨基]-5-(4-羟基-3,5-二甲氧苯基)-5,8,8a,9-四氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]二噁唑-6(5aH)-酮盐酸(1:1) | 127882-79-5

• 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
• 中文名称: (5R,5aR,8aS,9S)-9-[(4-氨基苯基)氨基]-5-(4-羟基-3,5-二甲氧苯基)-5,8,8a,9-四氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]二噁唑-6(5aH)-酮盐酸(1:1)
• 英文名称: 4'-O-demethyl-4β-(4''-aminoanilino)-4-desoxypodophyllotoxin chloride
• 英文别名: (5S,5aS,8aR,9R)-5-(4-aminoanilino)-9-(4-hydroxy-3,5-dimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one;hydron;chloride
• CAS: 127882-79-5
• 化学式: C₂₇H₂₆N₂O₇*ClH
• 分子量: 526.974
• InChiKey: UCWYAMAHWNCEOU-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：

  N-苄氧羰基-L-酪氨酸 、 (5R,5aR,8aS,9S)-9-[(4-氨基苯基)氨基]-5-(4-羟基-3,5-二甲氧苯基)-5,8,8a,9-四氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]二噁唑-6(5aH)-酮盐酸(1:1) 在 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 为溶剂， 以48%的产率得到benzyl N-[(2S)-1-[4-[[(5S,5aS,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]amino]anilino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]carbamate
  参考文献：
  名称：

  抗肿瘤药。第227部分：对新型4'-O-去甲基-表鬼臼毒素作为靶向拓扑异构酶II的抗肿瘤药物的研究。

  摘要：

  合成并评估了八种新颖的表鬼臼毒素衍生物（6-13），这些衍生物旨在克服耐药性并增强对拓扑异构酶II的抑制作用。与原型分子依托泊苷（1）相比，这些化合物中的两种（7和8）显示出更好的临床前活性，包括细胞生长抑制，细胞杀伤和体外拓扑异构酶II抑制。他们还保留了目前正在临床评估中的表鬼臼毒素衍生物GL-331（4）的优异抗药性。

  DOI：

  10.1016/j.bmc.2004.03.067
• 作为产物：
  描述：

  4'-去甲基表鬼臼毒素 在 palladium on activated charcoal 硫酸氢甲酯 、 氢气 、 sodium iodide 作用下， 以 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 4.0h， 生成 (5R,5aR,8aS,9S)-9-[(4-氨基苯基)氨基]-5-(4-羟基-3,5-二甲氧苯基)-5,8,8a,9-四氢呋喃并[3',4':6,7]萘并[2,3-d][1,3]二噁唑-6(5aH)-酮盐酸(1:1)
  参考文献：
  名称：

  抗肿瘤药。第227部分：对新型4'-O-去甲基-表鬼臼毒素作为靶向拓扑异构酶II的抗肿瘤药物的研究。

  摘要：

  合成并评估了八种新颖的表鬼臼毒素衍生物（6-13），这些衍生物旨在克服耐药性并增强对拓扑异构酶II的抑制作用。与原型分子依托泊苷（1）相比，这些化合物中的两种（7和8）显示出更好的临床前活性，包括细胞生长抑制，细胞杀伤和体外拓扑异构酶II抑制。他们还保留了目前正在临床评估中的表鬼臼毒素衍生物GL-331（4）的优异抗药性。

  DOI：

  10.1016/j.bmc.2004.03.067

文献信息

• Identification of Novel 4′-O-Demethyl-epipodophyllotoxin Derivatives as Antitumor Agents Targeting Topoisomerase II
  作者：Wenli Xi、Hua Sun、Kenneth F. Bastow、Zhiyan Xiao、Kuo-Hsiung Lee

  DOI：10.3390/molecules27155029

  日期：——

  compounds (11, 18, 27 and 28) induced protein-linked DNA break (PLDB) levels higher than those of GL-331 (6) and 2, and are assumed to be topoisomerase II (topo II) poisons more potent than 6 and 2. Compound 28, a potent topo II poison highly effective against KBvin cells, was further evaluated with a panel of tumor cells and was most active against HepG2. This compound also exhibited apparent in vivo

  4'- O-去甲基表鬼臼毒素（DMEP）的C4变异是优化该类化合物抗肿瘤谱的有效方法。因此，合成了两个系列的新型 DMEP 衍生物，正如预期的那样，这些衍生物的抗肿瘤谱随不同的 C4 取代基而变化。值得注意的是，大多数化合物显示出对依托泊苷 (2) 抗性 KBvin 细胞的显着抑制作用。其中四种化合物（11、18、27和28） 诱导的蛋白质连接 DNA 断裂 (PLDB) 水平高于 GL-331 ( 6 ) 和2，并被认为是拓扑异构酶 II (topo II) 的毒性更强大于6和2. 化合物28是一种对 KBvin 细胞非常有效的强效拓扑 II 毒物，用一组肿瘤细胞进一步评估，对 HepG2 最有效。该化合物还在肝癌 22 (H22) 小鼠模型中表现出明显的体内抗肿瘤功效。结果表明，DMEP 的 C4 衍生是鉴定具有优化抗肿瘤谱的强效拓扑 II 抑制剂的可行方法。
• 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.
• Antitumor agents—CLXXIII. Synthesis and evaluation of camptothecin-4β-amino-4′-O-demethyl epipodophyllotoxin conjugates as inhibitors of mammalian DNA topoisomerases and as cytotoxic agents
  作者：Kenneth F. Bastow、Hui-Kang Wang、Yung-Chi Cheng、Kuo-Hsiung Lee

  DOI：10.1016/s0968-0896(97)00102-8

  日期：1997.8

  Two conjugates composed of a camptothecin and a 4'-O-demethyl epipodophyllotoxin derivative joined by an imine linkage were prepared and evaluated as inhibitors of mammalian DNA topoisomerases I and II. Target compounds stimulated cleavable complex formation with both types of enzyme in vitro although activities were reduced at least twofold relative to the activity of unconjugated constituents. The behavior of the most active conjugate as an inhibitor of cell growth closely resembled both topoisomerase I- and II- inhibitory components in that the compound displayed a combined spectrum of activity against various drug-resistant KB sublines. Cytotoxic activity and selectivity were largely retained through conjugation, the exception being a lower than expected activity against a pleiotrophic multidrug-resistant subline. The induced levels and the properties of cellular protein-associated DNA complexes were consistent with topoisomerase involvement and with the in vitro cleavage assay results. Based on the present findings, conjugation afforded cleavable complex-forming topoisomerase inhibitors which display dual target specificity and a broad spectrum of cytotoxic activity against drug-resistant cells. (C) 1997 Published by Elsevier Science Ltd.
• 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：——