(E)-3-(2-((1S,5R,6R,8aR)-6-hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-oxodecahydronaphthalen-1-yl)ethylidene)dihydrofuran-2(3H)-one

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 内酯类
• 英文名称: (E)-3-(2-((1S,5R,6R,8aR)-6-hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-oxodecahydronaphthalen-1-yl)ethylidene)dihydrofuran-2(3H)-one
• 英文别名: (3E)-3-[2-[(1S,4aS,5R,6R,8aR)-6-hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-oxo-3,4,4a,6,7,8-hexahydro-1H-naphthalen-1-yl]ethylidene]oxolan-2-one
• 化学式: C₁₉H₂₈O₅
• 分子量: 336.428
• InChiKey: HLAHWWXOCUKRHM-VHMLWWRMSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  24
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.79
• 拓扑面积：
  83.8
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  穿心莲内酯 在 吡啶 、 对甲苯磺酸 、 臭氧 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 24.18h， 生成 (E)-3-(2-((1S,5R,6R,8aR)-6-hydroxy-5-(hydroxymethyl)-5,8a-dimethyl-2-oxodecahydronaphthalen-1-yl)ethylidene)dihydrofuran-2(3H)-one
  参考文献：
  名称：

  Specificity and Inhibitory Mechanism of Andrographolide and Its Analogues as Antiasthma Agents on NF-κB p50

  摘要：

  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.

  DOI：

  10.1021/np5007179

文献信息

• 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.