4'-O-demethyl-4β-(4''-carboxyanilino)-4-desoxypodophyllotoxin | 152833-18-6

• 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'-O-demethyl-4β-(4''-carboxyanilino)-4-desoxypodophyllotoxin
• 英文别名: 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]benzoic acid
• CAS: 152833-18-6
• 化学式: C₂₈H₂₅NO₉
• 分子量: 519.508
• InChiKey: CZXDFQJUHGPKOF-LVEBQJTPSA-N

物化性质

• 沸点：
  769.1±60.0 °C(predicted)
• 密度：
  1.453±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.6
• 重原子数：
  38
• 可旋转键数：
  6
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.29
• 拓扑面积：
  133
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  对羟基苯乙胺 、 4'-O-demethyl-4β-(4''-carboxyanilino)-4-desoxypodophyllotoxin 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82%的产率得到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]-N-[2-(4-hydroxyphenyl)ethyl]benzamide
  参考文献：
  名称：

  Antitumor Agents. 234. Design, Synthesis, and Biological Evaluation of Novel 4β-[(4‘ ‘-Benzamido)-Amino]-4‘-O-Demethyl-Epipodophyllotoxin Derivatives

  摘要：

  A series of 4beta-[(4"-benzamido)-amino]-4'-O-demethyl-epipodophyllotoxin derivatives (11-23) were designed to enhance DNA topoisomerase II inhibition, overcome drug resistance, and modulate water solubility of etoposide (1) analogues. The target compounds were synthesized and evaluated for their effects against DNA topoisomerase II and KB or 1-resistant KB-7d tumor cells in tissue culture. As compared with 1, most compounds showed superior inhibition against both KB and KB-7d cells. Nine compounds (13-18, 20-22) induced higher levels of cellular protein-linked DNA breaks than did 1. Ten compounds selected from these and related derivatives were further examined for their antitumor spectra and drug-resistance profiles. Like 1, these compounds selectively inhibited the growth of KB (nasopharyngeal) and 1A9 (ovarian) tumor cells. More notably, they retained inhibitory activity against etoposide-, camptothecin-, and paclitaxel-resistant KB or 1A9 subclones. In general, these C-4-modified new derivatives exhibited superior activity profiles, particularly against drug-resistant cell lines, to those of 1. Preliminary metabolism studies on compounds 16 and 20 revealed that 20 was relatively resistant to metabolism by rat serum and liver enzymes, while 16 was metabolically unstable.

  DOI：

  10.1021/jm030609l
• 作为产物：
  描述：

  4'-去甲基表鬼臼毒素 在 氢溴酸 、 barium carbonate 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 4'-O-demethyl-4β-(4''-carboxyanilino)-4-desoxypodophyllotoxin
  参考文献：
  名称：

  Antitumor Agents. 148. Synthesis and Biological Evaluation of Novel 4.beta.-Amino Derivatives of Etoposide with Better Pharmacological Profiles

  摘要：

  A series of novel 4 beta-amino derivatives of etoposide (1), which can form water-soluble salts and demonstrate excellent activity against mdr- and topo II-resistant cell lines, have been synthesized. Compared with etoposide; compounds 5-6, 8, and 10-16 show comparable or greater inhibition of human DNA topo II. In a cellular protein-DNA complex formation assay, compounds 5-6, 8, 10-14, and 16 are more potent than 1. A dose-response study of 8 shows that it is 20 times more active in formation of protein-linked DNA breaks than etoposide. Furthermore, both 8 and its free base 7 were found to be highly active toward etoposide-resistant KB cell lines. All compounds were also evaluated in vitro against a total of 56 human tumor cell lines derived from seven cancer types. Comparison of the log(10) GI(50) mean graph midpoints of 5-19 (-4.89 to -7.30) with that of 1 (-4.08) shows these new analogs to be 6-1659-fold more active than 1.

  DOI：

  10.1021/jm00030a003

文献信息

• Antitumor agents. Part 227: Studies on novel 4′-O-demethyl-epipodophyllotoxins as antitumor agents targeting topoisomerase II
  作者：Zhiyan Xiao、Kenneth F Bastow、John R Vance、Kuo-Hsiung Lee

  DOI：10.1016/j.bmc.2004.03.067

  日期：2004.6

  epipodophyllotoxin derivatives (6-13), which were designed to overcome drug resistance and enhance topoisomerase II inhibition, were synthesized and evaluated. Two of these compounds (7 and 8) showed better preclinical activity profiles, including cell growth inhibition, cell killing, and in vitro topoisomerase II inhibition, as compared to the prototype molecule etoposide (1). They also retained the superior drug-resistance

  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。
• Design and synthesis of novel cytotoxic podophyllotoxin derivatives
  作者：Wen Li Xi、Qian Cai、Yan Bo Tang、Hua Sun、Zhi Yan Xiao

  DOI：10.1016/j.cclet.2010.03.040

  日期：2010.10

  moieties on the cytotoxicity of podophyllotoxin derivatives, novel 4- N - and 4- C -substituted 4′- O -demethylepipodophyllotoxin derivatives were designed and synthesized. All the compounds were tested against A549 and MCF-7 tumor cells in vitro , and six compounds showed significant cytotoxicity. The most active compound 9f was superior to GL-331, and exhibited potent cytotoxicity with IC 50 value

  摘要为了研究不同的C4键部分对鬼臼毒素衍生物的细胞毒性的影响，设计合成了4-N-和4-C-取代的4'-O-去甲基表鬼臼毒素衍生物。所有化合物均在体外针对A549和MCF-7肿瘤细胞进行了测试，其中六种化合物显示出显着的细胞毒性。活性最高的化合物9f优于GL-331，并具有较强的细胞毒性，IC 50值为10 -7 mol / L。
• Antitumor agents. 256. Conjugation of paclitaxel with other antitumor agents: Evaluation of novel conjugates as cytotoxic agents
  作者：Kyoko Nakagawa-Goto、Seikou Nakamura、Kenneth F. Bastow、Alexander Nyarko、Chieh-Yu Peng、Fang-Yu Lee、Fang-Chen Lee、Kuo-Hsiung Lee

  DOI：10.1016/j.bmcl.2007.02.051

  日期：2007.5

  Sixteen different taxoid conjugates were prepared by linking various anticancer compounds, including camptothecin (CPT), epipodophyllotoxin (EP), colchicine (COL), and glycyrrhetinic acid (GA), at the 2'- or 7-position on paclitaxel (TXL, 1) through an ester, imine, amine, or amide bond. Newly synthesized conjugates were evaluated for cytotoxic activity against replication of several human tumor cell lines. Among them, TXL-CPT conjugates, 8-10, were more potent than TXL itself against the human prostate carcinoma cell line PC-3 (ED50 = 14.8, 3.1, 19.4 nM compared with 55.5 nM), and conjugate 10 was also 8-fold more active than TXL against the LN-CAP prostate cancer cell line. These compounds also possessed anti-angiogenesis ability as well as lower inhibitory effects against a normal cell line (MRC-5). Thus, conjugates 8-10 are possible antitumor drug candidates, particularly for prostate cancer. (c) 2007 Elsevier Ltd. All rights reserved.
• WATER-SOLUBLE ETOPOSIDE ANALOGS AND METHODS OF USE THEREOF
  申请人：Lee Kuo-Hsiung

  公开号：US20070123475A1

  公开（公告）日：2007-05-31

  Etoposide analogs with improved water-solubility such as 4′-O-Demethyl-4′-(N′,N′-dimethyl-glycyl)-4β-(4″-nitroanilino)-4-desoxy-podophyllotoxin (8) and 4′-O-Demethyl-4′-(N′,N′-dimethyl-glycyl)-4β-(4″-fluoroanilino)-4-desoxy-podophyllotoxin (9) are described, along with pharmaceutical formulations containing the same, methods of use thereof, and intermediates and methods of making the same.
• US7176236B2
  申请人：——

  公开号：US7176236B2

  公开（公告）日：2007-02-13