6,7-O,O-demethylene-4β-(4"-nitroanilino)-4'-O-demethyl-4-desoxypodophyllotoxin | 138355-85-8

• 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: 6,7-O,O-demethylene-4β-(4"-nitroanilino)-4'-O-demethyl-4-desoxypodophyllotoxin
• 英文别名: (3aS,4S,9R,9aR)-6,7-dihydroxy-9-(4-hydroxy-3,5-dimethoxyphenyl)-4-(4-nitroanilino)-3a,4,9,9a-tetrahydro-3H-benzo[f][2]benzofuran-1-one
• CAS: 138355-85-8
• 化学式: C₂₆H₂₄N₂O₉
• 分子量: 508.485
• InChiKey: WLMQDRMQLUGOEB-QQJYNPJZSA-N

物化性质

• 沸点：
  804.3±65.0 °C(Predicted)
• 密度：
  1.485±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  37
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  163
• 氢给体数：
  4
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  4,5-二氯邻苯二胺 、 6,7-O,O-demethylene-4β-(4"-nitroanilino)-4'-O-demethyl-4-desoxypodophyllotoxin 在 Celite 、 silver carbonate 作用下， 以 乙醇 为溶剂， 反应 1.0h， 以4%的产率得到(4R,5R,9S,10S)-17,18-dichloro-4-(4-hydroxy-3,5-dimethoxyphenyl)-10-(4-nitroanilino)-7-oxa-14,21-diazapentacyclo[11.8.0.03,11.05,9.015,20]henicosa-1(21),2,11,13,15,17,19-heptaen-6-one
  参考文献：
  名称：

  Antitumor Agents. 164. Podophenazine, 2‘‘,3‘‘-Dichloropodophenazine, Benzopodophenazine, and Their 4β-p-Nitroaniline Derivatives as Novel DNA Topoisomerase II Inhibitors

  摘要：

  We report here the synthesis and biological evaluation of novel DNA topoisomerase II inhibitors, podophenazine (8), 2'',3''-dichloropodophenazine (9), and benzopodophenazine (10), and their 4 beta-p-nitroaniline derivatives 13-15. Among these, 4'-O-demethyl-4 beta-(4'''-nitroanilino)-4-desoxypodophenazine (13) and 4'-O-demethyl-2'',3''-dichloro-4 beta-(4'''-nitroanilino)-4-desoxypodophenazine (14) were found to inhibit KB cells at sub-micromolar concentrations (IC50 = 0.11 +/- 0.03 and 0.48 +/- 0.17 mu M, respectively). Against KB/7d cells (a pleiotrophic multiple drug-resistant subclone selected with etoposide which has reduced level of topoisomerase II), only compound 13 out of a target series maintained activity in the sub-micromolar concentration range with a IC50 value of 0.56 +/- 0.13 mu M. The differential toxicity ratio for 13 [IC50(KB/7d)/IC50(KB)] was similar to 5. Unlike etoposide and its congeners, compounds 13 and 14 were found to be weak inhibitors of the catalytic activity of topoisomerase II (IC100 = >100 and >150 mu M, respectively). In vitro protein-linked DNA complex formation assay revealed that 13 and 14, respectively, induced marginal response (13 at 1 mu M, 320.3 +/- 124.5 cpm; 13 at 50 mu M, 308.8 +/- 139.9 cpm; 13 at 100 mu M, 446.0 +/- 153.5 cpm) and no response (14 at 1 mu M, 104.9 +/- 52.6 cpm; 14 at 50 mu M, 103.3 +/- 42.6 cpm; 14 at 100 mu M, 101.4 +/- 35.2 cpm) compared to the enzyme control. On the basis of these results, we conclude that the mechanism of enzyme inhibition of these compounds is distinct from that of etoposide and its congeners. We are currently investigating the mechanism(s) of action of compounds 13 and 14 as well as synthesizing other derivatives in order to better characterize structure-activity relationships of this series of compounds.

  DOI：

  10.1021/jm950548u
• 作为产物：
  描述：

  鬼臼毒素 在 氢溴酸 、 三氯化硼 、 barium carbonate 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 5.0h， 生成 6,7-O,O-demethylene-4β-(4"-nitroanilino)-4'-O-demethyl-4-desoxypodophyllotoxin
  参考文献：
  名称：

  Antitumor agents. 124. New 4.beta.-substituted aniline derivatives of 6,7-O,O-demethylene-4'-O-demethylpodophyllotoxin and related compounds as potent inhibitors of human DNA topoisomerase II

  摘要：

  A series of 6,7-O,O-demethylene-4'-O-demethyl-4-beta-(substituted anilino)-4-desoxypodophyllotoxins (18-23), 6,7-O,O-demethylene-6,7-O,O-dimethyl-4'-O-demethyl-4-beta-(substituted anilino)-4-desoxypodophyllotoxins (28-31), and their corresponding 4'-O-methyl analogues (12-17 and 24-27) 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. Compounds 18-23 are 2-fold more potent than etoposide and compounds 12, 16, 17, 30, and 31 are as active as etoposide in their inhibition of the human DNA topoisomerase II. Compounds 19 and 20 and 29-31 are as active or more active than etoposide in causing protein-linked DNA breakage. These results indicate that a free C-4' hydroxy group is essential for the DNA breakage activity, and that the hydroxyl groups at C-6 and -7 positions may be involved in an interaction which is responsible for the inhibitory activity of DNA topoisomerase II. The maintenance of an intact methylene dioxy-type ring-A system would contribute to enhanced activity. In addition, the sterically less hindered substitution at C-6 and C-7 positions may be important for optimal interactions with DNA topoisomerase II. There is no correlation between the ability of these compounds to inhibit DNA topoisomerase II and their ability to cause protein-linked DNA breaks in cells. This may relate to the difference in uptake of these compounds. The better correlation was observed between the protein-linked DNA breaks and the cytotoxicity in KB cells of these compounds.

  DOI：

  10.1021/jm00083a010