4-(2-(((3R,5aS,6R,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethyl)morpholine

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 异戊烯醇脂质
• 英文名称: 4-(2-(((3R,5aS,6R,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethyl)morpholine
• 英文别名: 4-[2-[[(1R,4S,5R,8S,9R,10S,12R,13R)-1,5,9-trimethyl-11,14,15,16-tetraoxatetracyclo[10.3.1.04,13.08,13]hexadecan-10-yl]oxy]ethyl]morpholine
• 化学式: C₂₁H₃₅NO₆
• 分子量: 397.512
• InChiKey: BYMNFJKAXZHAJK-RCQQOWRMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  28
• 可旋转键数：
  4
• 环数：
  6.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  58.6
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  dihydroartemisinin 在 三氟化硼乙醚 、 potassium carbonate 、 sodium iodide 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 19.0h， 生成 4-(2-(((3R,5aS,6R,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)ethyl)morpholine
  参考文献：
  名称：

  双氢青蒿素C-10半缩醛衍生物作为Toll样受体4拮抗剂的构效关系研究

  摘要：

  双氢青蒿素(DHA)，一种从传统中草药青蒿中分离出来的天然产物作为一种抗疟疾感染的临床一线药物，最近被发现是一种 Toll 样受体 4 (TLR4) 拮抗剂。然而，DHA 的 TLR4 拮抗活性是适度的，并且表现出细胞毒性。在这项工作中，探索了 DHA 作为 TLR4 拮抗剂的构效关系 (SAR)。由于破坏倍半萜内过氧化物支架显着损害了 TLR4 拮抗活性，分子动力学分析表明 C-10 羟基与髓细胞分化因子 2 (MD2) 的 E72 形成氢键以防止其深入 MD2，因此 DHA 的 SAR 为专注于 C-10 半缩醛位置。随着在 C10 位置延长直链烷烃链的长度，DHA 类似物的 TLR4 拮抗活性先增加后降低，最好的 TLR4 拮抗作用发生在 3-4 个碳的碳链长度处。相比之下，DHA 类似物的细胞毒性随着线性烷烃链长度的增加而增加。以取代卤素为末端官能团的DHA衍生物的TLR4拮抗活性

  DOI：

  10.1016/j.bioorg.2021.105107

文献信息

• Synthesis, antimalarial activity and cytotoxicity of 10-aminoethylether derivatives of artemisinin
  作者：Theunis T. Cloete、J. Wilma Breytenbach、Carmen de Kock、Peter J. Smith、Jaco C. Breytenbach、David D. N’Da

  DOI：10.1016/j.bmc.2012.06.014

  日期：2012.8

  artemisinin using conventional and microwave assisted syntheses, and their structures were confirmed by NMR and HRMS. All derivatives proved to be active against both strains of the parasite. The highest overall activity was displayed by the short chain aromatic derivative 8 (IC50 = 1.44 nM), containing only one nitrogen atom, while long chain polyamine derivatives were found to have the lowest activity against

  在这项研究中，合成了一系列 11 种青蒿素 10-氨基乙醚衍生物，并测定了它们对氯喹敏感 (D10) 和抗性 (Dd2)恶性疟原虫菌株的抗疟活性。该化合物是通过使用常规和微波辅助合成方法通过青蒿素 C-10 处的乙醚桥引入具有不同链长连接基的脂肪族、脂环族和芳香族胺基团来制备的，其结构经核磁共振和 HRMS 确证。所有衍生物都被证明对两种寄生虫都有活性。短链芳香族衍生物 8 (IC 50 = 1.44 nM)，仅含有一个氮原子，而长链多胺衍生物对两种菌株的活性最低。发现 IC 50、p K a值和电阻指数 (RI)之间存在有趣的相关性。
• Synthesis and Antimalarial Activity of Artemisinin Derivatives Containing an Amino Group
  作者：Ying Li、Yuan-Ming Zhu、Hong-Jian Jiang、Jian-Ping Pan、Guang-Shao Wu、Jin-Ming Wu、Yun-Lin Shi、Jun-De Yang、Bo-An Wu

  DOI：10.1021/jm990552w

  日期：2000.4.1

  In search of water-soluble artemisinin derivatives that are more stable than sodium artesunate, over 30 derivatives containing an amino group (compounds 3-5) were synthesized and tested in mice. All products tested (except 5a and 5b) are the beta isomers. These basic compounds combined with organic acids (oxalic acid, maleic acid, etc.) to yield the corresponding salts. Generally, the maleates have better solubility in water than the corresponding oxalates. The aqueous solutions of these salts can be kept at room temperature for several weeks without any discernible decomposition. Compounds 3f, 3h, and 3r are much more active against P. berghei than artesunic acid by oral administration and therefore were further tested in monkeys. However, their oral efficacies are poorer than that of artesunic acid against P. knowlesi in rhesus monkeys. It is interesting to note that 3f, 3h, and 3r showed much lower efficacies against P. berghei when they were administered subcutaneously than orally.
• Structure-activity relationship study of dihydroartemisinin C-10 hemiacetal derivatives as Toll-like receptor 4 antagonists
  作者：Shuo Wang、Hongshuang Wang、Cong Lin、Tianshu Zhang、Jingwei Gao、Siru Wu、Yibo Wang、Hongyuan Li、Weihong Min、Chunlei Liu、Xiaohui Wang

  DOI：10.1016/j.bioorg.2021.105107

  日期：2021.9

  recently been discovered as a Toll-like Receptor 4 (TLR4) antagonist. However, the TLR4 antagonistic activity of DHA is modest and it exhibits cellular toxicity. In this work, the structure-activity relationship (SAR) of DHA as TLR4 antagonist was explored. Since destroying the sesquiterpene endoperoxide scaffold substantially compromised the TLR4 antagonistic activity and molecular dynamics analysis

  双氢青蒿素(DHA)，一种从传统中草药青蒿中分离出来的天然产物作为一种抗疟疾感染的临床一线药物，最近被发现是一种 Toll 样受体 4 (TLR4) 拮抗剂。然而，DHA 的 TLR4 拮抗活性是适度的，并且表现出细胞毒性。在这项工作中，探索了 DHA 作为 TLR4 拮抗剂的构效关系 (SAR)。由于破坏倍半萜内过氧化物支架显着损害了 TLR4 拮抗活性，分子动力学分析表明 C-10 羟基与髓细胞分化因子 2 (MD2) 的 E72 形成氢键以防止其深入 MD2，因此 DHA 的 SAR 为专注于 C-10 半缩醛位置。随着在 C10 位置延长直链烷烃链的长度，DHA 类似物的 TLR4 拮抗活性先增加后降低，最好的 TLR4 拮抗作用发生在 3-4 个碳的碳链长度处。相比之下，DHA 类似物的细胞毒性随着线性烷烃链长度的增加而增加。以取代卤素为末端官能团的DHA衍生物的TLR4拮抗活性