3-[2-((4aR,6aS,7R,10aS,10bR)-3,3,6a,10b-Tetramethyl-8-methylene-decahydro-naphtho[2,1-d][1,3]dioxin-7-yl)-eth-(E)-ylidene]-3H-furan-2-one | 727723-05-9

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 类固醇和类固醇衍生物
• 英文名称: 3-[2-((4aR,6aS,7R,10aS,10bR)-3,3,6a,10b-Tetramethyl-8-methylene-decahydro-naphtho[2,1-d][1,3]dioxin-7-yl)-eth-(E)-ylidene]-3H-furan-2-one
• 英文别名: (E)-3-(2-((4aR,6aS,7R,10bR)-3,3,6a,10b-tetramethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)ethylidene)furan-2(3H)-one
• CAS: 727723-05-9
• 化学式: C₂₃H₃₂O₄
• 分子量: 372.505
• InChiKey: CWXMCFPGVMZSDV-LUBPEKPSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.91
• 重原子数：
  27.0
• 可旋转键数：
  2.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  44.76
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  3-[2-((4aR,6aS,7R,10aS,10bR)-3,3,6a,10b-Tetramethyl-8-methylene-decahydro-naphtho[2,1-d][1,3]dioxin-7-yl)-eth-(E)-ylidene]-3H-furan-2-one 在 potassium permanganate 作用下， 以 四氢呋喃 为溶剂， 反应 1.0h， 生成 2-((4aR,6aS,7R,10aS,10bR)-3,3,6a,10b-tetramethyl-8-methylenedecahydro-1H-naphtho[2,1-d][1,3]dioxin-7-yl)acetaldehyde
  参考文献：
  名称：

  新的合成耳鼻喉科从他们的抗炎活性的穿心莲内酯和评价-labdane二萜衍生物

  摘要：

  合成了两类穿心莲内酯衍生物，其中含氮杂环，酚和芳香酸为内酯环的生物等排体。18种受试化合物中的8种对RAW264.7巨噬细胞中LPS诱导的NO生成的抑制作用强于氢化可的松。其中，化合物8m表现出最强的抑制作用，IC 50为3.38±1.03μM。构效关系（SARs）表明，用小分子酚取代内酯环可以提高抗炎效果。此外，化合物8m显着降低促炎细胞因子IL-1β和IL-6的水平，而不影响细胞存活，降低iNOS和COX-2的表达，并下调IκBα的水平和磷酸化以及IκBα的表达NF-κB。它还阻止了LPS诱导的巨噬细胞中NF-κB的核易位。因此，化合物8m的抗炎机制与抑制COX-2，iNOS和NF-κB信号通路有关。

  DOI：

  10.1016/j.ejmech.2018.11.002
• 作为产物：
  描述：

  14-O-acetyl-3,18-O-isopropylideneandrographolide 在 4-二甲氨基吡啶 作用下， 以 二氯甲烷 为溶剂， 以80%的产率得到3-[2-((4aR,6aS,7R,10aS,10bR)-3,3,6a,10b-Tetramethyl-8-methylene-decahydro-naphtho[2,1-d][1,3]dioxin-7-yl)-eth-(E)-ylidene]-3H-furan-2-one
  参考文献：
  名称：

  Novel routes for the generation of structurally diverse labdane diterpenes from andrographolide

  摘要：

  Andrographolide 1, the major constituent of the Indian medicinal plant Andrographis paniculata (Acanthaceae) was converted into the key intermediate 4 by selective oxidative degradation of the C-12,13 olefin bond. The aldehyde functional group present in 4 has been utilized for synthesizing a number of structurally diverse labdane diterpenes. Synthesis and in vitro cytotoxic activity results of the compounds prepared are discussed. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetlet.2004.04.142

文献信息

• Nickel-Mediated Inter- and Intramolecular Reductive Cross-Coupling of Unactivated Alkyl Bromides and Aryl Iodides at Room Temperature
  作者：Chang-Song Yan、Yu Peng、Xiao-Bo Xu、Ya-Wen Wang

  DOI：10.1002/chem.201200190

  日期：2012.5.7

  A nickel‐mediated intermolecular reductive cross‐coupling reaction of unactivated alkyl bromides and aryl iodides at room temperature has been developed and successfully extended to less explored intramolecular versions and tandem cyclization‐intermolecular cross‐coupling. Highly stereoselective (or stereospecific) synthesis of linear‐fused perhydrofuro[2,3‐b]furan (pyran) and spiroketal skeletons

  已开发出室温下未活化的烷基溴和芳基碘的镍介导的分子间还原性交叉偶联反应，并成功地扩展到较少探索的分子内版本和串联环化-分子间交叉偶联。线性稠合的全氢呋喃[2,3- b ]呋喃（吡喃）和螺环骨架的高度立体选择性（或立体定向）合成可以快速获得这些有用的结构单元，这在相关天然产物的合成中可能具有潜在的价值。给出了形成连续立体中心的合理解释。
• From irreversible to reversible covalent inhibitors: Harnessing the andrographolide scaffold for anti-inflammatory action
  作者：Quy T.N. Tran、Daniel W.S. Tan、W.S. Fred Wong、Christina L.L. Chai

  DOI：10.1016/j.ejmech.2020.112481

  日期：2020.10

  we present our effort directed towards understanding the contribution of chemical reactivity to biological potency to rationally design new covalent inhibitors based on the ent-ladane andrographolide scaffold for anti-inflammatory action. Specifically, a series of andrographolide derivatives comprising various Michael acceptors was developed and their thiol reactivity was assayed under various chemical

  具有延长作用的共价药物通常显示出优越的功效，但是缺乏优化其结构和电子特征的综合策略。在此，我们提出我们引向理解化学反应的贡献生物效价合理设计基础上，新的共价抑制剂努力耳鼻喉科-ladane穿心莲内酯支架的抗炎作用。具体而言，开发了包含各种迈克尔受体的一系列穿心莲内酯衍生物，并在各种化学和生物学条件下测定了它们的硫醇反应性。基于细胞的SAR研究允许在更复杂的系统中评估抑制剂的功效，这在使用分离的蛋白质或肽进行的传统共价药物开发中通常受到限制。我们的体外研究确定烯酮17是最有前途的候选药物，与铅类穿心莲内酯相比，它具有强大的抗炎活性和优越的安全性。其与生物硫醇的迈克尔加成反应后的可逆性导致更可预测的药理反应。另外，当在LPS诱导的急性肺损伤模型中进行测试时，有17种药物在低至0.3 mg / kg的剂量下表现出良好的体内功效。鉴于化学反应性和生物效能之间的良好平衡，烯酮17潜在地提供了基于天然产物化学的新治疗选择，可用于治疗炎症。
• Synthesis and evaluation of andrographolide derivatives as potent anti-osteoporosis agents in vitro and in vivo
  作者：Songxuan Zhang、Yuting Zhang、Yuying Fang、Hao Chen、Mengjiao Hao、Qingyun Tan、Chen Hu、Huihao Zhou、Jun Xu、Qiong Gu

  DOI：10.1016/j.ejmech.2021.113185

  日期：2021.3

  In this work, we found that 14-deoxy-11,12-didehydroandrographolide (2), a derivative of andrographolide (AP, 1), had greatly reduced cytotoxicity compared with AP and exhibited moderate anti-osteoclastogenesis activity. Thirty compounds were synthesized by introducing anti-osteoporosis chemotypes at C-19 of 2. Six of them exhibited stronger inhibition of osteoclastogenesis than AP. Of note, compound

  在这项工作中，我们发现穿心莲内酯的衍生物（AP，1）14-脱氧-11,12-二氢加氢穿心莲内酯（2）与AP相比具有大大降低的细胞毒性，并表现出中等的抗破骨细胞生成活性。通过在2的C-19处引入抗骨质疏松症的化学型，合成了30种化合物。他们中的六个表现出比AP更强的破骨细胞抑制作用。值得注意的是，化合物12g表现出最强的活性，IC 50值为0.35μM。通过12g处理，破骨细胞特异性基因（例如TRAcP，CTSK，NFATc1和MMP-9）的表达水平也降低了。此外，蛋白质印迹和免疫荧光分析表明该化合物12g通过下调RANKL诱导的NF-κB信号通路抑制破骨细胞分化。在卵巢切除（OVX）雌性小鼠模型中，化合物12g显着改善了骨质流失。因此，化合物12g显示出有希望的体内功效和低毒性，表明其治疗骨质疏松症的治疗潜力。
• 穿心莲内酯化合物及其制备方法和用途
  申请人：沈阳药科大学

  公开号：CN110963894B

  公开（公告）日：2022-09-02

  本发明属于医药技术领域，涉及穿心莲内酯衍生物及其制备方法和用途。具体涉及一种新的具有抗炎症活性的化合物、其异构体或其药学上可接受的盐，以及含有该化合物的药物组合物和制备方法。以及这些化合物在制备治疗和/或预防炎症药物中的应用。所述的化合物、及其异构体或其药学上可接受的盐如通式(I)所示，其中R如权利要求书和说明书所述。
• Specificity and Inhibitory Mechanism of Andrographolide and Its Analogues as Antiasthma Agents on NF-κB p50
  作者：Van Sang Nguyen、Xin Yi Loh、Hadhi Wijaya、Jigang Wang、Qingsong Lin、Yulin Lam、Wai-Shiu Fred Wong、Yu Keung Mok

  DOI：10.1021/np5007179

  日期：2015.2.27

  Andrographolide (1) is a diterpenoid lactone with an a,beta-unsaturated lactone group that inhibits NF kappa B DNA binding. Andrographolide reacts with the nucleophilic Cys62 of NF-kappa B p50 through a Michael addition at the Delta(12(13)) exocylic double bond to form a covalent adduct. Using computer docking, site-directed mutagenesis, and mass spectrometry, the noncovalent interactions between andrographolide and additional binding site residues other than Cys62 were found to be essential for the covalent incorporation of andrographolide. Furthermore, the addition reaction of andrographolide on Cys62 was highly dependent on the redox conditions and on the vicinity of nearby, positively charged Arg residues in the conserved RxxRxR motif. The reaction mechanisms of several of the analogues were determined, showing that 14-deoxy-11,12-didehydroandrographolide (8) reacts with NF-kappa B p50 via a novel mechanism distinct from andrographolide. The noncovalent interaction and redox environment of the binding site should be considered, in addition to the electrophilicity, when designing a covalent drug. Analogues similar in structure appear to use distinct reaction mechanisms and may have very different cytotoxicities, e.g., compound 6.