3-(((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)propan-1-ol

• 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: 3-(((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)propan-1-ol
• 英文别名: 3-[[(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]propan-1-ol
• 化学式: C₁₈H₃₀O₆
• 分子量: 342.433
• InChiKey: LRFWDUDDKZOVSW-QOBNMGNYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  24
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  66.4
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-(((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)propan-1-ol 在 吡啶 、 4-二甲氨基吡啶 作用下， 以 乙醚 、 二氯甲烷 为溶剂， 生成 methyl (3-(((3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl)oxy)propyl) succinate
  参考文献：
  名称：

  青蒿素的基于连接子的半琥珀酸酯衍生物：小鼠多药耐药性约氏疟原虫的合成和抗疟疾评估（1）

  摘要：

  青蒿琥酯5是双氢青蒿素2的半琥珀酸酯衍生物，是青蒿素1的唯一在临床上有用的水溶性衍生物。然而，作为一种乳糖醇酯，它在碱性水溶液中迅速水解回二氢青蒿素，这一反应严重限制了其实用性。已经准备了一系列可能更稳定的基于接头的半琥珀酸酯衍生物12a – i和14a – c。该过程涉及双氢青蒿素与各种二醇和聚乙二醇的酸催化反应，得到羟基官能化的醚7a – i和10a –c及其进一步衍生为半琥珀酸酯12a - i和14a - c。评估了羟基官能化的醚7a – i和10a – c以及它们的半琥珀酸酯衍生物12a – i和14a – c在瑞士小鼠中对多药耐药的约氏疟原虫的抗疟活性。这些半琥珀酸酯衍生物中的几种已显示出非常有前途的活性。半琥珀酸酯衍生物12f和12i，该系列中两种活性最高的化合物以24 mg / kg×4天的剂量为感染疟疾的小鼠提供100％的保护，因此效力是青蒿琥酯的两倍，后者以48 mg /

  DOI：

  10.1021/jm2010699
• 作为产物：
  描述：

  dihydroartemisinin 、 1,3-丙二醇 在 三氟化硼乙醚 作用下， 以 二氯甲烷 为溶剂， 反应 7.0h， 以68%的产率得到3-(((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)propan-1-ol
  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

• Mechanism-Based Development of New Antimalarials: Synthesis of Derivatives of Artemisinin Attached to Iron Chelators
  作者：Sumalee Kamchonwongpaisan、Sumpan Paitayatat、Yodhathai Thebtaranonth、Prapin Wilairat、Yongyuth Yuthavong

  DOI：10.1021/jm00013a007

  日期：1995.6

  Various derivatives of artemisinin covalently linked to iron chelators were synthesized, and their antimalarial activities were evaluated. Although results show no indication that the presence of an iron chelator in the vicinity of artemisinin potentiates its action, the linked compounds prepared still retain comparable activities to that of artemisinin.
• Antimalarial activity of new ethers and thioethers of dihydroartemisinin
  作者：B Venugopalan、PJ Karnik、CP Bapat、DK Chatterjee、N Iyer、D Lepcha

  DOI：10.1016/0223-5234(96)88287-0

  日期：1995.1

  Various ethers and thioethers of dihydroartemisinin were prepared by treating dihydroartemisinin with hydroxy alkyl, substituted phenol, hydroxy aralkyl, hydroxy alkynyl and hydroxy heteroalkyl or thiols in the presence of BF(3)Et(2)O. The thioethers 64 and 65 were further oxidised to the respective sulfoxides. These derivatives were tested in the Plasmodium berghei K-173-infected mice and some active compounds were tested in chloroquine-resistant P yoelii nigeriensis (NS)-infected mice. Initially the compounds were administered subcutaneously and subsequently by the oral route. The antimalarial activity of the compounds 22, 23, 36, 66 and 79 were found to be comparable to that of arteether when tested in the K-173-infected mice. These compounds also showed activity in the P y nigeriensis (NS)-infected mice.
• Artemisinins target the intermediate filament protein vimentin for human cytomegalovirus inhibition
  作者：Sujayita Roy、Arun Kapoor、Fei Zhu、Rupkatha Mukhopadhyay、Ayan Kumar Ghosh、Hyun Lee、Jennifer Mazzone、Gary H. Posner、Ravit Arav-Boger

  DOI：10.1074/jbc.ra120.014116

  日期：2020.10

  The antimalarial agents artemisinins inhibit cytomegalovirus (CMV) in vitro and in vivo, but their target(s) has been elusive. Using a biotin-labeled artemisinin, we identified the intermediate filament protein vimentin as an artemisinin target, validated by detailed biochemical and biological assays. We provide insights into the dynamic and unique modulation of vimentin, depending on the stage of human CMV (HCMV) replication. In vitro, HCMV entry and viral progeny are reduced in vimentin-deficient fibroblasts, compared with control cells. Similarly, mouse CMV (MCMV) replication in vimentin knockout mice is significantly reduced compared with controls in vivo, confirming the requirement of vimentin for establishment of infection. Early after HCMV infection of human foreskin fibroblasts vimentin level is stable, but as infection proceeds, vimentin is destabilized, concurrent with its phosphorylation and virus-induced calpain activity. Intriguingly, in vimentin-overexpressing cells, HCMV infection is reduced compared with control cells. Binding of artesunate, an artemisinin monomer, to vimentin prevents virus-induced vimentin degradation, decreasing vimentin phosphorylation at Ser-55 and Ser-83 and resisting calpain digestion. In vimentin-deficient fibroblasts, the anti-HCMV activity of artesunate is reduced compared with controls. In summary, an intact and stable vimentin network is important for the initiation of HCMV replication but hinders its completion. Artesunate binding to vimentin early during infection stabilizes it and antagonizes subsequent HCMV-mediated vimentin destabilization, thus suppressing HCMV replication. Our target discovery should enable the identification of vimentin-binding sites and compound moieties for binding.
• Linker-Based Hemisuccinate Derivatives of Artemisinin: Synthesis and Antimalarial Assessment against Multidrug-Resistant <i>Plasmodium yoelii nigeriensis</i> in Mice
  作者：Chandan Singh、Rani Kanchan、Sandeep Chaudhary、Sunil K. Puri

  DOI：10.1021/jm2010699

  日期：2012.2.9

  Artesunic acid 5, the hemisuccinate derivative of dihydroartemisinin 2, is the only clinically useful water-soluble derivative of artemisinin 1. However, being a lactol ester, it is rapidly hydrolyzed back to dihydroartemisinin in aqueous alkaline solution, a reaction that seriously limits its utility. A new series of potentially more stable linker-based hemisuccinate derivatives 12a–i and 14a–c have been prepared

  青蒿琥酯5是双氢青蒿素2的半琥珀酸酯衍生物，是青蒿素1的唯一在临床上有用的水溶性衍生物。然而，作为一种乳糖醇酯，它在碱性水溶液中迅速水解回二氢青蒿素，这一反应严重限制了其实用性。已经准备了一系列可能更稳定的基于接头的半琥珀酸酯衍生物12a – i和14a – c。该过程涉及双氢青蒿素与各种二醇和聚乙二醇的酸催化反应，得到羟基官能化的醚7a – i和10a –c及其进一步衍生为半琥珀酸酯12a - i和14a - c。评估了羟基官能化的醚7a – i和10a – c以及它们的半琥珀酸酯衍生物12a – i和14a – c在瑞士小鼠中对多药耐药的约氏疟原虫的抗疟活性。这些半琥珀酸酯衍生物中的几种已显示出非常有前途的活性。半琥珀酸酯衍生物12f和12i，该系列中两种活性最高的化合物以24 mg / kg×4天的剂量为感染疟疾的小鼠提供100％的保护，因此效力是青蒿琥酯的两倍，后者以48 mg /
• 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