6,7-O,O-demethylenepodophyllotoxin | 1174-97-6

• 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: 6,7-O,O-demethylenepodophyllotoxin
• 英文别名: 3',4'-demethylenepodophyllotoxin；6,7-O-Demethylen-podophyllotoxin；(3aR,4R,9R,9aR)-4,6,7-trihydroxy-9-(3,4,5-trimethoxyphenyl)-3a,4,9,9a-tetrahydro-3H-benzo[f]isobenzofuran-1-one；(3aR,4R,9R,9aR)-4,6,7-trihydroxy-9-(3,4,5-trimethoxyphenyl)-3a,4,9,9a-tetrahydro-3H-benzo[f][2]benzofuran-1-one
• CAS: 1174-97-6
• 化学式: C₂₁H₂₂O₈
• 分子量: 402.401
• InChiKey: AIEQNTGIFXFNRB-BTINSWFASA-N

物化性质

• 熔点：
  222-224 °C
• 沸点：
  652.7±55.0 °C(Predicted)
• 密度：
  1.396±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  29
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  115
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  6,7-O,O-demethylenepodophyllotoxin 在 4-二甲氨基吡啶 、 potassium carbonate 、 N,N'-二异丙基碳二亚胺 作用下， 以 二氯甲烷 、 丙酮 为溶剂， 生成 [(3aR,4R,9R,9aR)-6,7-dimethoxy-1-oxo-9-(3,4,5-trimethoxyphenyl)-3a,4,9,9a-tetrahydro-3H-benzo[f][2]benzofuran-4-yl] octanoate
  参考文献：
  名称：

  Synthesis and Quantitative Structure–Activity Relationship (QSAR) Study of Novel 4-Acyloxypodophyllotoxin Derivatives Modified in the A and C Rings as Insecticidal Agents

  摘要：

  In continuation of our program aimed at the discovery and development of natural-product-based insecticidal agents, we have synthesized three series of novel 4-acyloxy compounds derived from podophyllotoxin modified in the A and C rings, which is isolated as the main secondary metabolite from the roots and rhizomes of Podophyllum hexandrum. Their insecticidal activity was preliminarily evaluated against the pre-third-instar larvae of Mythimna separata in vivo. Compound 9g displayed the best promising insecticidal activity. It revealed that cleavage of the 6,7-methylenedioxy group of podophyllotoxin will lead to a less active compound and that the C-4 position of podophyllotoxin was the important modification location. A quantitative structure activity relationship (QSAR) model was developed by genetic algorithm combined with multiple linear regression (GA-MLR). For this model, the squared correlation coefficient (R-2) is 0.914, the leave-one-out cross-validation correlation coefficient (Q(LOO)(2)) is 0.881, and the root-mean-square error (RMSE) is 0.024. Five descriptors, BEHm2, Mor14v, Wap, G1v, and RDF020e, are likely to influence the biological activity of these compounds. Among them, two important ones are BEHm2 and Mor14v. This study will pave the way for further design, structural modification, and development of podophyllotoxin derivatives as insecticidal agents.

  DOI：

  10.1021/jf305011n
• 作为产物：
  描述：

  鬼臼毒素 在 三氯化硼 、 calcium carbonate 作用下， 以 二氯甲烷 、 水 、 丙酮 为溶剂， 反应 2.25h， 以80%的产率得到6,7-O,O-demethylenepodophyllotoxin
  参考文献：
  名称：

  在A环中修饰的鬼臼毒素类似物的合成和细胞毒性。

  摘要：

  已经制备了几种缺乏亚甲二氧基或环木脂素骨架的A环功能不同的鬼臼毒素衍生物，并评估了它们对四种肿瘤细胞系（P-388，A-549，HT-29和MEL-28）的细胞毒活性）。他们中的大多数保持其细胞毒性在microM水平。

  DOI：

  10.1016/s0223-5234(02)00007-7

文献信息

• Synthesis of podophyllotoxin A-ring pyridazine analogue
  作者：Emmanuel Bertounesque、Thierry Imbert、Claude Monneret

  DOI：10.1016/0040-4020(96)00862-9

  日期：1996.11

  Podophyllotoxin A-ring pyridazine analogue 3 has been constructed in nine steps from (−)-podophyllotoxin. The Stille reaction was exploited to generate the key intermediate 4.

  鬼臼毒素A环哒嗪类似物3已从（-）-鬼臼毒素开始九步构建。利用Stille反应生成关键中间体4。
• Biosynthesis of podophyllum lignans—i. cinnamic acid precursors of podophyllotoxin in podophyllum hexandrum
  作者：David E. Jackson、Paul M. Dewick

  DOI：10.1016/s0031-9422(00)82603-5

  日期：1984.1
• In vivo immunosuppressive activity of some cyclolignans
  作者：Marina Gordaliza、MaAngeles Castro、JoséMa Miguel del Corral、MaLuisa López-Vázquez、Arturo San Feliciano、Glynn T. Faircloth

  DOI：10.1016/s0960-894x(97)10072-5

  日期：1997.11

  Several podophyllotoxin-related cyclolignans, either lacking the lactone ring or the methylenedioxy grouping, have been prepared and evaluated for their immunosuppressive (IMS) activity in the mouse allogeneic MLR in vitro test and in the in vivo techniques Graft vs Host Reaction (GVHR) and Skin Grafting (SG). The results obtained show that three cyclolignans fairly prevent splenomegaly in comparison with control animals and also promoted tolerance to grafting, being the first time that the in vivo LMS activity of cyclolignas is reported. (C) 1997 Elsevier Science Ltd.
• Antitumor Agents. 164. Podophenazine, 2‘‘,3‘‘-Dichloropodophenazine, Benzopodophenazine, and Their 4β-<i>p</i>-Nitroaniline Derivatives as Novel DNA Topoisomerase II Inhibitors
  作者：Sung Jin Cho、Yoshiki Kashiwada、Kenneth F. Bastow、Yung-Chi Cheng、Kuo-Hsiung Lee

  DOI：10.1021/jm950548u

  日期：1996.1.1

  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.
• 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
  作者：Zhe-Qing Wang、Hong Hu、Hong-Xin Chen、Yung-Chi Cheng、Kuo Hsiung Lee

  DOI：10.1021/jm00083a010

  日期：1992.3

  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.