(3aR,4S,9R,9aR)-4,6,7-三羟基-9-(4-羟基-3,5-二甲氧苯基)-3a,4,9,9a-四氢萘并[2,3-c]呋喃-1(3H)-酮 | 138456-91-4

• 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: (3aR,4S,9R,9aR)-4,6,7-三羟基-9-(4-羟基-3,5-二甲氧苯基)-3a,4,9,9a-四氢萘并[2,3-c]呋喃-1(3H)-酮
• 英文名称: 6,7-O,O-demethylene-4'-O-demethylepipodophyllotoxin
• 英文别名: 4-Demethyl-6,7-demethylene-1-epipodophyllotoxin；(3aR,4S,9R,9aR)-4,6,7-trihydroxy-9-(4-hydroxy-3,5-dimethoxyphenyl)-3a,4,9,9a-tetrahydro-3H-benzo[f][2]benzofuran-1-one
• CAS: 138456-91-4
• 化学式: C₂₀H₂₀O₈
• 分子量: 388.374
• InChiKey: SMPCOLOECPREKW-HQKIHSOMSA-N

物化性质

• 沸点：
  687.9±55.0 °C(Predicted)
• 密度：
  1.479±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  126
• 氢给体数：
  4
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (3aR,4S,9R,9aR)-4,6,7-三羟基-9-(4-羟基-3,5-二甲氧苯基)-3a,4,9,9a-四氢萘并[2,3-c]呋喃-1(3H)-酮 在 sodium azide 、 三氟乙酸 作用下， 生成 (3aS,4S,9R,9aR)-4-azido-6,7-dimethoxy-9-(3,4,5-trimethoxyphenyl)-3a,4,9,9a-tetrahydronaphtho[2,3-c]furan-1(3H)-one
  参考文献：
  名称：

  新型鬼臼毒素衍生物的合成及其抗HIV-1活性。

  摘要：

  为了探索鬼臼毒素化合物类别的生物活性范围，设计，合成了鬼臼毒素的一系列新衍生物，这些衍生物是含有司他夫定和不同结构鬼臼毒素类似物的结合物，并评估了它们的抗HIV-1活性。体外。在这些化合物中，19d和19c显示最高的抗HIV-1活性，EC（50）值为0.17和0.29 microM，TI值分别为466.9和354.5。

  DOI：

  10.1016/j.bmcl.2006.11.070
• 作为产物：
  描述：

  去氧鬼臼毒素 在 N-溴代丁二酰亚胺(NBS) 、 水 、 三氯化硼 、 barium carbonate 、 过氧化苯甲酰 作用下， 反应 6.5h， 生成 (3aR,4S,9R,9aR)-4,6,7-三羟基-9-(4-羟基-3,5-二甲氧苯基)-3a,4,9,9a-四氢萘并[2,3-c]呋喃-1(3H)-酮
  参考文献：
  名称：

  Antitumor Agents. I. DNA Topoisomerase II Inhibitory Activity and the Structural Relationship of Podophyllotoxin Derivatives as Antitumor Agents.

  摘要：

  合成了多种来自脱氧髓鞘素（DPT）的紫苑毒素衍生物，以研究其在体外的生物重要性（细胞毒性、对 DNA 拓扑异构酶 II 的影响和微管聚合影响）与在体内的抗肿瘤活性（L 1210）之间的结构关系。DPT 的完整 6, 7-亚甲基二氧基基团是抑制微管聚合和拓扑异构酶 II 所必需的。DPT 的 4'-酚羟基对于抑制 DNA 拓扑异构酶 II 是必不可少的，而对 DNA 拓扑异构酶 II 的抑制作用导致了高细胞毒性。DPT 在 1 位置引入氨基烷氧基团增强了对 DNA 拓扑异构酶 II 的抑制活性和细胞毒性，导致对微管聚合的抑制活性消失。在 L 1210 移植小鼠中对紫苑毒素衍生物的抗肿瘤测试结果表明：1）只要与抑制微管聚合相关，强细胞毒性本身并不是评估体内抗肿瘤活性的良好指征。DNA 拓扑异构酶 II 的抑制作用对体内抗肿瘤活性有贡献；2）为了评估紫苑毒素衍生物，需详细测定体外的细胞毒性及对 DNA 拓扑异构酶 II 和微管聚合的抑制作用。

  DOI：

  10.1248/cpb.40.2720

文献信息

• Synthesis and evaluation of novel podophyllotoxin analogs
  作者：Jie Li、Hui Ming Hua、Yan Bo Tang、Shipeng Zhang、Emika Ohkoshi、Kuo-Hsiung Lee、Zhi yan Xiao

  DOI：10.1016/j.bmcl.2012.05.033

  日期：2012.7

  Because prior studies have shown inconsistency between structure-activity relationships for podophyllotoxin derivatives as topoisomerase II inhibitors and cytotoxic agents, eight novel podophyllotoxin analogs were synthesized to further explore the effects of structural variations on both A and D rings on activity. The new compounds contain a 4,5-dimethoxy substituted A ring and opened D-ring variants and were prepared by appropriate functional and stereochemical operations at the methylenedioxy group, C7, C8, and C80. Four compounds (15, 18, 21 and 22) demonstrated noticeable inhibitory activity against A549, DU145, KB and KBvin tumor cells, and the most active compound 18 showed IC50 values less than 10 mu g/mL. (C) 2012 Elsevier Ltd. All rights reserved.
• 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.
• Synthesis and anti-HIV-1 activities of novel podophyllotoxin derivatives
  作者：Shi-Wu Chen、Yun-Hua Wang、Yan Jin、Xuan Tian、Yong-Tang Zheng、Du-Qiang Luo、Yong-Qiang Tu

  DOI：10.1016/j.bmcl.2006.11.070

  日期：2007.4

  the range of biological activities of the podophyllotoxin compound class, a novel series of derivatives of podophyllotoxin, which were conjugates containing stavudine and different structural podophyllotoxin analogues, were designed, synthesized, and evaluated for their anti-HIV-1 activities in vitro. Among these compounds, 19d and 19c showed the highest anti-HIV-1 activities with EC(50) values of 0

  为了探索鬼臼毒素化合物类别的生物活性范围，设计，合成了鬼臼毒素的一系列新衍生物，这些衍生物是含有司他夫定和不同结构鬼臼毒素类似物的结合物，并评估了它们的抗HIV-1活性。体外。在这些化合物中，19d和19c显示最高的抗HIV-1活性，EC（50）值为0.17和0.29 microM，TI值分别为466.9和354.5。
• Antitumor Agents. I. DNA Topoisomerase II Inhibitory Activity and the Structural Relationship of Podophyllotoxin Derivatives as Antitumor Agents.
  作者：Tadafumi TERADA、Katsuhiko FUJIMOTO、Makoto NOMURA、Jun-ichi YAMASHITA、Takashi KOBUNAI、Setsuo TAKEDA、Konstanty WIERZBA、Yuji YAMADA、Hideo YAMAGUCHI

  DOI：10.1248/cpb.40.2720

  日期：——

  Various podophyllotoxin derivatives from desoxypodophyllotoxin (DPT) were synthesized to examine the structural relationships between the biological significance (cytotoxic effect, effects on DNA topoisomerase II and tubulin polymerization) in vitro and antitumor activity in vivo (L 1210).An intact 6, 7-methylenedioxy group of DPT is necessary to inhibit tubulin polymerization and topoisomerase II. 4'-Phenolic hydroxyl group of DPT is essential to inhibit DNA topoisomerase II and the inhibitory effect on DNA topoisomerase II contributes to a high cytotoxicity.The introduction of an aminoalkoxy group at 1-position of DPT enhances the inhibitory activity against DNA topoisomerase II and cytotoxic effect, causing the inhibitory activity against tubulin polymerization to disappear. The results of antitumor test in mice bearing L 1210 on podophyllotoxin derivatives suggest the following : 1) the strong cytotoxic effect itself is not a good indication of antitumor activity in vivo as long as it is associated with inhibition of tubulin polymerization. DNA topoisomerase II inhibitory effect contributes to an antitumor activity in vivo; 2) detailed measurements of cytotoxicity and inhibition on DNA topoisomerase II and tubulin polymerization in vitro are necessary to evaluate podophyllotoxin derivatives.

  合成了多种来自脱氧髓鞘素（DPT）的紫苑毒素衍生物，以研究其在体外的生物重要性（细胞毒性、对 DNA 拓扑异构酶 II 的影响和微管聚合影响）与在体内的抗肿瘤活性（L 1210）之间的结构关系。DPT 的完整 6, 7-亚甲基二氧基基团是抑制微管聚合和拓扑异构酶 II 所必需的。DPT 的 4'-酚羟基对于抑制 DNA 拓扑异构酶 II 是必不可少的，而对 DNA 拓扑异构酶 II 的抑制作用导致了高细胞毒性。DPT 在 1 位置引入氨基烷氧基团增强了对 DNA 拓扑异构酶 II 的抑制活性和细胞毒性，导致对微管聚合的抑制活性消失。在 L 1210 移植小鼠中对紫苑毒素衍生物的抗肿瘤测试结果表明：1）只要与抑制微管聚合相关，强细胞毒性本身并不是评估体内抗肿瘤活性的良好指征。DNA 拓扑异构酶 II 的抑制作用对体内抗肿瘤活性有贡献；2）为了评估紫苑毒素衍生物，需详细测定体外的细胞毒性及对 DNA 拓扑异构酶 II 和微管聚合的抑制作用。