4β-azido-4-deoxy-4′-demethylepipodophyllotoxin | 117604-05-4

• 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
• 英文名称: 4β-azido-4-deoxy-4′-demethylepipodophyllotoxin
• 英文别名: 4β-azido-4'-demethylepipodophyllotoxin；4β-azido-4-deoxy-4'-demethypodophyllotoxin；4β-azido-4-deoxy-4'-demethylpodophyllotoxin；(5R,5aR,8aS,9S)-9-azido-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,5a,8a,9-tetrahydrofuro[3',4': 6,7]naphtho[2,3-d][1,3]dioxol-6(8H)-one；(5S,5aS,8aR,9R)-5-azido-9-(4-hydroxy-3,5-dimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one
• CAS: 117604-05-4
• 化学式: C₂₁H₁₉N₃O₇
• 分子量: 425.398
• InChiKey: JGNBIEBOJZWEKG-JHQYFNNDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  97.8
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  4β-azido-4-deoxy-4′-demethylepipodophyllotoxin 在 palladium on activated charcoal 氢气 作用下， 以70%的产率得到(5R,5aR,8aS,9S)-9-amino-5-(4-hydroxy-3,5-dimethoxyphenyl)-5,5a,8a,9-tetrahydrofuro[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6(8H)-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：

  鬼臼毒素 在 三(2-氯乙基)胺 、 三氟化硼乙醚 、 氢溴酸 作用下， 以 二氯甲烷 为溶剂， 生成 4β-azido-4-deoxy-4′-demethylepipodophyllotoxin
  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

文献信息

• Synthesis and Anticancer Activity of Glucosylated Podophyllotoxin Derivatives Linked via 4β-Triazole Rings
  作者：Cheng-Ting Zi、Feng-Qing Xu、Gen-Tao Li、Yan Li、Zhong-Tao Ding、Jun Zhou、Zi-Hua Jiang、Jiang-Miao Hu

  DOI：10.3390/molecules181113992

  日期：——

  A series of 4β-triazole-linked glucose podophyllotoxin conjugates have been designed and synthesized by employing a click chemistry approach. All the compounds were evaluated for their anticancer activity against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW480) using MTT assays. Most of these triazole derivatives have good anticancer activity. Among them, compound 35 showed the highest potency against all five cancer cell lines tested, with IC50 values ranging from 0.59 to 2.90 μM, which is significantly more active than the drug etoposide currently in clinical use. Structure-activity relationship analysis reveals that the acyl substitution on the glucose residue, the length of oligoethylene glycol linker, and the 4'-demethylation of podophyllotoxin scaffold can significantly affect the potency of the anticancer activity. Most notably, derivatives with a perbutyrylated glucose residue show much higher activity than their counterparts with either a free glucose or a peracetylated glucose residue.

  通过点击化学方法，设计并合成了系列4β-三氮唑连接的葡萄糖鬼臼毒素缀合物。所有化合物均通过MTT法对其在五种人癌细胞系（HL-60，SMMC-7721，A-549，MCF-7，SW480）中的抗癌活性进行了评估。这些三氮唑衍生物大多具有良好的抗癌活性。其中，化合物35对所有五种癌细胞系的活性最高，IC50值在0.59至2.90 μM之间，其活性显著高于临床使用的药物依托泊苷。结构-活性关系分析显示，葡萄糖残基上的酰基取代、聚乙烯 glycol 链的长度以及鬼臼毒素骨架的4'-脱甲基化对抗癌活性的强度有显著影响。特别值得注意的是，具有完全丁酰化的葡萄糖残基的衍生物比具有游离葡萄糖或完全乙酰化葡萄糖残基的对照组活性高得多。
• Antitumor agents. 120. New 4-substituted benzylamine and benzyl ether derivatives of 4'-O-demethylepipodophyllotoxin as potent inhibitors of human DNA topoisomerase II
  作者：Xiao Ming Zhou、Zhe Qing Wang、Jang Yang Chang、Hong Xing Chen、Yung Chi Cheng、Kuo Hsiung Lee

  DOI：10.1021/jm00116a001

  日期：1991.12

  The most active compounds are 14, 16, and 17, which are more than 2-fold more potent than 1. The results indicated that a basic unsubstituted 4 beta-benzylamino moiety is structurally required for the enhanced activity. Replacement of the benzyl nitrogen with oxygen gave compounds (23 and 24) which are inactive. The ability of these compounds to inhibit human DNA topoisomerase II and to cause protein-linked

  已经合成了许多具有各种4β-N-或4β-O-苄基的新的4'-O-去甲基表鬼臼毒素衍生物，并评估了其对人DNA拓扑异构酶II的抑制活性以及在引起细胞凋亡方面的活性。蛋白质相关的DNA断裂。4种β-N-苄基衍生物9-22通常具有活性，或具有比依托泊苷（1）更高的活性。活性最高的化合物是14、16和17，它们的效力比1强2倍以上。结果表明，增强的活性在结构上需要碱性的未取代的4β-苄基氨基部分。用氧代替苄基氮得到惰性的化合物（23和24）。
• Synthesis and antitumor activity of camptothecin- 4β-triazolopodophyllotoxin conjugates
  作者：Cheng-Ting Zi、Liu Yang、Fa-Wu Dong、Qing-Hua Kong、Zhong-Tao Ding、Jun Zhou、Zi-Hua Jiang、Jiang-Miao Hu

  DOI：10.1080/14786419.2018.1538223

  日期：2020.8.17

  Two new compounds (9 and 10) having a camptothecin (CPT) analog conjugated to the 4β-azido-4-deoxypodophyllotixin analog by untilizing the copper-catalyzed azide-alkyne cycloadditon (CuAAC) reaction, and were evaluated for their cytotoxicity against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7 and SW480) using the MTT (3-(4,5-dimethyl-thiahiazo-2-yl)-2,5-diphenyltetrazolium

  将喜树碱（CPT）类似物偶联至4β-叠氮基4-脱氧鬼臼毒素类似物直到铜催化的叠氮化物-炔烃环己二酮（CuAAC）反应偶联后的两个新化合物（9和10），并评估其对面板的细胞毒性MTT（3-（4,5-二甲基-噻唑基-2-基）-2,5-二苯基四唑鎓）检测五个人类癌细胞系（HL-60，SMMC-7721，A-549，MCF-7和SW480）溴化物）分析。两种新型缀合物显示出弱的细胞毒性，化合物10显示出对测试的HL-60细胞系的强效作用，IC 50值为17.69±0.19μM。该化合物表明其作为抗癌剂具有进一步开发的潜力。
• Design, Synthesis, and Cytotoxicity of Perbutyrylated Glycosides of 4β-Triazolopodophyllotoxin Derivatives
  作者：Cheng-Ting Zi、Zhen-Hua Liu、Gen-Tao Li、Yan Li、Jun Zhou、Zhong-Tao Ding、Jiang-Miao Hu、Zi-Hua Jiang

  DOI：10.3390/molecules20023255

  日期：——

  A series of novel perbutyrylated glycosides of 4β-triazolopodophyllotoxin derivatives were synthesized by utilizing the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction. Evaluation of cytotoxicity against a panel of five human cancer cell lines (HL-60, SMMC-7721, A-549, MCF-7, SW480) using the MTT assay shows that some of these glycosylated derivatives have good anticancer activity. Among the synthesized compounds, compound 21a shows the highest activity, with IC50 values ranging from 0.49 to 6.70 μM, which is more potent than the control drugs etoposide and cisplatin. Compound 21a is characterized by a perbutyrylated α-D(+)-galactosyl residue, the absence of an additional linking spacer between the sugar residue and the triazole ring, as well as a 4'-OH group on the E ring of the podophyllotoxin scaffold.

  一系列新颖的4β-三唑基鬼臼毒素衍生物的全丁酰化糖苷通过铜催化的叠氮-炔环加成反应（CuAAC）合成。采用MTT法对五种人癌细胞系（HL-60、SMMC-7721、A-549、MCF-7、SW480）进行的细胞毒性评估显示，这些糖基化衍生物中的一些具有良好的抗癌活性。在合成的化合物中，化合物21a显示出最高的活性，IC50值在0.49至6.70 μM之间，比对照药物依托泊苷和顺铂更为强效。化合物21a的特点是具有全丁酰化的α-D(+)-半乳糖基残基，糖残基与三唑环之间没有额外的连接间隔，并且在鬼臼毒素骨架的E环上有一个4'-OH基团。
• 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。