4'-O-demethyl-4β-(p-aminoanilino)-4-desoxypodophyllotoxin

• 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-(p-aminoanilino)-4-desoxypodophyllotoxin
• 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
• 化学式: C₂₇H₂₆N₂O₇
• 分子量: 490.513
• InChiKey: CVYPFSWTHXCTKR-LVEBQJTPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  36
• 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：
  3
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  4'-O-demethyl-4β-(p-aminoanilino)-4-desoxypodophyllotoxin 、 2'-(4-formyl)benzoyl paclitaxel 以 苯 为溶剂， 反应 24.0h， 以70%的产率得到
  参考文献：
  名称：

  Antitumor agents 210. synthesis and evaluation of taxoid–epipodophyllotoxin conjugates as novel cytotoxic agents

  摘要：

  Five compounds composed of a taxoid (paclitaxel or cephalomannine) and a 4'-O-demethyl epipodophyllotoxin derivative joined by an imine linkage were prepared and evaluated as cytotoxic agents and inhibitors of mammalian DNA topoisomerase II. Compounds 12 and 14-16 exhibited comparable or better activity than the unconjugated epipodophyllotoxin derivatives in most tumor cell lines, and 12, 15, and 16 also showed enhanced activity against paclitaxel-resistant cells. Compound 13, which contains an epipodophyllotoxin moiety at both the taxoid 2' and 7 positions, did not stimulate protein-DNA breaks, but was 2-fold more potent than 12 and 15 and comparable to GL-331 in the topo II inhibitory assay. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(01)00206-1
• 作为产物：
  描述：

  对苯二胺 、 鬼臼毒素 在 sodium iodide 、 甲烷磺酸 、 三乙胺 作用下， 以 二氯甲烷 、 四氢呋喃 为溶剂， 反应 24.25h， 以20%的产率得到4'-O-demethyl-4β-(p-aminoanilino)-4-desoxypodophyllotoxin
  参考文献：
  名称：

  一种从天然产物鬼臼毒素中衍生的新型细胞毒性偶联物作为直接靶蛋白双重抑制剂

  摘要：

  天然产物是设计新型高效分子实体的理想基础。鬼臼毒素是一种天然存在的环木脂素，从生物活性的角度来看，它是一种具有高度多功能性的天然产物。基于其独特的化学结构，已经合成了具有与该化合物相关的原始抗肿瘤特性的不同衍生物，即抑制微管蛋白聚合和通过对环木脂素骨架的结构修饰产生抗拓扑异构酶 II 活性。在这份报告中，我们提出了一种新的共轭物或杂交物，它在一个单一分子中化学结合了两种生物活性。化学设计基于我们的先导化合物鬼臼醛，作为微管蛋白聚合的抑制剂，以及依托泊苷，一种已批准的靶向拓扑异构酶 II 的抗肿瘤药物。已在不同实体瘤的几种细胞系中评估了新型合成杂交体的细胞毒性和选择性。此外，还通过分子对接方法评估了新型化合物的这些双重功能作用。

  DOI：

  10.3390/molecules25184258

文献信息

• Antitumor agents. 1771. Design, syntheses, and biological evaluation of novel etoposide analogs bearing pyrrolecarboxamidino group as DNA topoisomerase II inhibitors
  作者：Zheng Ji、Hui-Kang Wang、Kenneth F. Bastow、Xiao-Kang Zhu、Sung Jin Cho、Yung-Chi Cheng、Kuo-Hsiung Lee

  DOI：10.1016/s0960-894x(97)00060-7

  日期：1997.3

  Novel water-soluble 4 beta-amino-4'-O-demethylepipodophyllotoxin derivatives (6-12), designed to enhance minor groove binding ability, were synthesized and screened against NCI's in vitro disease-oriented human tumor cells. Among them, 4'-O-demethyl-4 beta-[N-(1 triple prime-methyl-4 triple prime-nitro-pyrrole-2 triple prime-carbonyl)-4 ''-aminoanilino]-4-desoxypodophyllotoxin (10) and its HCl salt (11) were found to exhibit potent cytotoxic activities (average log GI(50) = -6.91, -7.00, and -5.01 for 10, 11, and etoposide, respectively). Compounds 10 and 12 were further tested for their inhibitory activities against DNA topoisomerase II. Compound 10 again exhibited a superior activity profile compared to that of etoposide, displaying increased cytotoxicity against KB and KB-7d cells (ID50/LD(50) = 0.04/0.15 and 0.2/0.25 for KB and KB-7d cells, respectively), topoisomerase II inhibitory activity (12.5 mu M), and cellular protein DNA complex formation (225%). (C) 1997 Elsevier Science Ltd. All rights reserved.
• Antitumor agents 210. synthesis and evaluation of taxoid–epipodophyllotoxin conjugates as novel cytotoxic agents
  作者：Qian Shi、Hui-Kang Wang、Kenneth F Bastow、Yoko Tachibana、Ke Chen、Fang-Yu Lee、Kuo-Hsiung Lee

  DOI：10.1016/s0968-0896(01)00206-1

  日期：2001.11

  Five compounds composed of a taxoid (paclitaxel or cephalomannine) and a 4'-O-demethyl epipodophyllotoxin derivative joined by an imine linkage were prepared and evaluated as cytotoxic agents and inhibitors of mammalian DNA topoisomerase II. Compounds 12 and 14-16 exhibited comparable or better activity than the unconjugated epipodophyllotoxin derivatives in most tumor cell lines, and 12, 15, and 16 also showed enhanced activity against paclitaxel-resistant cells. Compound 13, which contains an epipodophyllotoxin moiety at both the taxoid 2' and 7 positions, did not stimulate protein-DNA breaks, but was 2-fold more potent than 12 and 15 and comparable to GL-331 in the topo II inhibitory assay. (C) 2001 Elsevier Science Ltd. All rights reserved.
• A Novel Cytotoxic Conjugate Derived from the Natural Product Podophyllotoxin as a Direct-Target Protein Dual Inhibitor
  作者：Ángela-Patricia Hernández、Paula Díez、Pablo A. García、Martín Pérez-Andrés、Pablo Ortega、Pablo G. Jambrina、David Díez、María Ángeles Castro、Manuel Fuentes

  DOI：10.3390/molecules25184258

  日期：——

  tubulin polymerization inhibition and arising anti-topoisomerase II activity from structural modifications on the cyclolignan skeleton. In this report, we present a novel conjugate or hybrid which chemically combines both biological activities in one single molecule. Chemical design has been planned based in our lead compound, podophyllic aldehyde, as an inhibitor of tubulin polymerization, and in

  天然产物是设计新型高效分子实体的理想基础。鬼臼毒素是一种天然存在的环木脂素，从生物活性的角度来看，它是一种具有高度多功能性的天然产物。基于其独特的化学结构，已经合成了具有与该化合物相关的原始抗肿瘤特性的不同衍生物，即抑制微管蛋白聚合和通过对环木脂素骨架的结构修饰产生抗拓扑异构酶 II 活性。在这份报告中，我们提出了一种新的共轭物或杂交物，它在一个单一分子中化学结合了两种生物活性。化学设计基于我们的先导化合物鬼臼醛，作为微管蛋白聚合的抑制剂，以及依托泊苷，一种已批准的靶向拓扑异构酶 II 的抗肿瘤药物。已在不同实体瘤的几种细胞系中评估了新型合成杂交体的细胞毒性和选择性。此外，还通过分子对接方法评估了新型化合物的这些双重功能作用。