(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 | 117507-84-3

• 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: (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
• 英文别名: 4β-amino-4'-demethyl-4-desoxypodophyllotoxin；4β-amino-4'-demethyl-epipodophyllotoxin；9-Amino-5-(4-hydroxy-3,5-dimethoxy-phenyl)-5,8,8a,9-tetrahydro-5aH-furo[3',4':6,7]naphtho[2,3-d][1,3]dioxol-6-one；(5S,5aS,8aR,9R)-5-amino-9-(4-hydroxy-3,5-dimethoxyphenyl)-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[5,6-f][1,3]benzodioxol-8-one
• CAS: 117507-84-3
• 化学式: C₂₁H₂₁NO₇
• 分子量: 399.4
• InChiKey: WZTRSUUEQXXWCN-JHQYFNNDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  29
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  110
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (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 在 palladium on activated charcoal 三乙烯二胺 、 咪唑 、 Dowex 50 x 20-200 ion-exchange resin 、 氢气 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 51.0h， 生成 N-[(5S,5aS,8aR,9R)-9-(4-hydroxy-3,5-dimethoxyphenyl)-8-oxo-5a,6,8a,9-tetrahydro-5H-[2]benzofuro[6,5-f][1,3]benzodioxol-5-yl]-4-aminobenzenesulfonamide
  参考文献：
  名称：

  Synthesis and Biological Activity of Sulfonamide Derivatives of Epipodophyllotoxin

  摘要：

  A series of novel 4beta-substituted sulfonamide derivatives of 4'-O-demethyl-4-desoxypodophyllotoxin has been synthesized. Their effects on human DNA topoisomerase II and, in some cases, on tubulin polymerization were evaluated. Compounds 8a, 8c, 8f, 8g, 8n, 8q, 8r, and 8s and the synthetic precursor 4 are potent topoisomerase II poisons that induce double-stranded breaks in DNA, with either improved or similar activity compared to etoposide. Only the amino precursor, compound 5, was slightly active in tubulin polymerization inhibition assays. We observed that the derivatives bearing an aromatic ring on the 4beta-sulfonamide substituent were either less cytotoxic or equivalent to the parent drug, while the sulfonamides containing an aliphatic side chain and the amino-sulfonamide derivatives, except 8d and 8g, exhibited increased cytoxicity compared to etoposide. In vivo, against the P388 leukemia and the A-549 orthotopic model of lung carcinoma, the most promising compounds were the morpholino- and the piperazino-containing sulfonamides derivatives 8r and 8s.

  DOI：

  10.1021/jm031117b
• 作为产物：
  描述：

  鬼臼毒素 在 palladium on activated charcoal sodium azide 、 baker's yeast 、 phosphate buffer 、 氢溴酸 、 氢气 、 三乙胺 、 barium carbonate 作用下， 以 乙醇 为溶剂， 反应 4.0h， 生成 (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：

  立体和化学选择性酶还原叠氮基官能团：面包酵母合成4-β-氨基鬼臼毒素类同系物

  摘要：

  通过使用贝克酵母在温和条件下以优异的产率立体选择性地生物催化还原4-叠氮基鬼臼毒素，合成了4β-氨基鬼臼毒素同源物。

  DOI：

  10.1016/s0040-4039(97)01582-7
• 作为试剂：
  描述：

  {benzyloxycarbonyl-[3-(benzyloxycarbonyl-{4-[benzyloxy-carbonyl-(3-benzyloxycarbonylaminopropyl)-amino]-butyl}-amino)-propyl]-amino}-acetic acid 、 (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 在 (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 作用下， 以53的产率得到
  参考文献：
  名称：

  Process for the preparation of (poly) aminoalkylaminoacetamide derivatives of epipodophyllotoxin useful for their applications in therapeutics as anticancer agent

  摘要：

  本发明涉及一种新的制备（聚）氨基烷基氨基乙酰胺衍生物和其盐的方法，其特征在于包括将4-氨基-4'-去甲基表地酚毒素与具有保护基的含胺反应物进行肽偶联的步骤。

  公开号：

  US08664409B2

文献信息

• 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）。
• [EN] ANTICANCER CONJUGATE<br/>[FR] CONJUGUÉ ANTICANCÉREUX
  申请人：ADAMED SP ZOO

  公开号：WO2014141094A1

  公开（公告）日：2014-09-18

  An anticancer conjugate, which comprises a fusion protein comprising domain (a), which is the functional fragment of a sequence of soluble human TRAIL (hTRAIL) protein beginning with an amino acid at a position not lower than hTRAIL95 or a sequence having at least 70% identity with said functional fragment, domain (b) which is the sequence of an effector peptide having proapoptotic, antiangiogenic, antiproliferative or pore forming activity, and conjugation domain (d) for attachment of a chemical compound selected from the group consisting of the sequences Cys Ala Ala Ala Cys Ala Ala Cys and Cys Ala Ala Cys Ala Ala Ala Cys, and a molecule of a chemical compound Z having antiblastic activity, which is attached to said conjugation domain (d) of said fusion protein directly or via a conjugation linker L.

  一种抗癌结合物，包括融合蛋白，该融合蛋白包括以下部分：（a）功能性片段，该片段是以不低于hTRAIL95位置的氨基酸开始的可溶性人类TRAIL（hTRAIL）蛋白序列的片段，或者具有与该功能性片段至少70%同源性的序列；（b）是具有促凋亡、抗血管生成、抗增殖或形成孔活性的效应肽序列；以及（d）用于连接来自以下序列的化学化合物的结合结构域，该序列包括Cys Ala Ala Ala Cys Ala Ala Cys和Cys Ala Ala Cys Ala Ala Ala Cys，以及具有抗肿瘤活性的化学化合物Z的分子，该分子附着在所述融合蛋白的结合结构域（d）上，直接或通过结合连接物L连接。
• 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。
• [EN] HUMAN TOPOISOMERASE II-TARGETING ORGANOPLATINUM COMPOUNDS<br/>[FR] COMPOSÉS D'ORGANOPLATINE CIBLANT LA TOPOISOMÉRASE II HUMAINE
  申请人：LI TSAI KUN

  公开号：WO2020037652A1

  公开（公告）日：2020-02-27

  Some organoplatinum compounds have been synthesized. These organoplatinum compounds are designed to be human Topoisomerase II-targeting drugs.

  一些有机铂化合物已经合成。这些有机铂化合物被设计为人类拓扑异构酶II靶向药物。
• Structure-based design, synthesis and biological testing of etoposide analog epipodophyllotoxin–N-mustard hybrid compounds designed to covalently bind to topoisomerase II and DNA
  作者：Arun A. Yadav、Xing Wu、Daywin Patel、Jack C. Yalowich、Brian B. Hasinoff

  DOI：10.1016/j.bmc.2014.09.014

  日期：2014.11

  docking a series of etoposide analog epipodophyllotoxin–N-mustard hybrid compounds were designed, synthesized and biologically characterized. These hybrids were designed to alkylate nucleophilic protein residues on topoisomerase II and thus produce inactive covalent adducts and to also alkylate DNA. The most potent hybrid had a mean GI50 in the NCI-60 cell screen 17-fold lower than etoposide. Using a variety

  靶向 DNA 拓扑异构酶 II 异构体和烷基化 DNA 的药物代表了两种机制不同且临床上重要的抗癌药物。在分子建模和对接的指导下，设计、合成和生物学表征了一系列依托泊苷类似物表鬼臼毒素-N-芥末杂化化合物。这些杂交体被设计为烷基化拓扑异构酶 II 上的亲核蛋白残基，从而产生无活性的共价加合物，并且也烷基化 DNA。最强大的杂交种的平均 GI 为50在 NCI-60 细胞筛选中，比依托泊苷低 17 倍。使用各种体外和基于细胞的测定，所有测试的杂交体都显示靶向拓扑异构酶 II。比较分析表明，这些杂种的 NCI 60 细胞生长抑制谱与它们所源自的依托泊苷和 N-芥末化合物相匹配。这些结果支持这样的结论，即杂种表现出的特征与同时靶向拓扑异构酶 II 和 DNA 一致。