8α-hydroxyhirsutinolide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氢呋喃
• 英文名称: 8α-hydroxyhirsutinolide
• 英文别名: 8Alpha-Hydroxyhirsutinolide；(1R,2E,8S,10R,11S)-8,11-dihydroxy-6-(hydroxymethyl)-1,10-dimethyl-4,14-dioxatricyclo[9.2.1.03,7]tetradeca-2,6-dien-5-one
• 化学式: C₁₅H₂₀O₆
• 分子量: 296.32
• InChiKey: HGVUPZFNJFDVQM-HEQUYQGPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.2
• 重原子数：
  21
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  96.2
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3,3-二甲基丙烯酸 、 8α-hydroxyhirsutinolide 在 4-二甲氨基吡啶 、 N,N'-二环己基碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 反应 24.0h， 以49%的产率得到((4S,6R,E)-4,7-dihydroxy-6,10-dimethyl-2-oxo-2,4,5,6,7,8,9,10-octahydro-7,10-epoxycyclodeca[b]furan-3-yl)methyl 3-methylbut-2-enoate
  参考文献：
  名称：

  Hirsutinolide Series Inhibit Stat3 Activity, Alter GCN1, MAP1B, Hsp105, G6PD, Vimentin, TrxR1, and Importin α-2 Expression, and Induce Antitumor Effects against Human Glioma

  摘要：

  We report that hirsutinolide series, 6, 7, 10, 11, 20, and 22, and the semisynthetic analogues, 30, 31, 33, and 36, inhibit constitutively active signal transducer and activator of transcription (Stat)3 and malignant glioma phenotype. A position 13 lipophilic ester group is required for activity. Molecular modeling and nuclear magnetic resonance structural analyses reveal direct hirsutinolide:Stat3 binding. One-hour treatment of cells with 6 and 22 also upregulated importin subunit alpha-2 levels and repressed translational activator GCN1, microtubule-associated protein (MAP) 1B, thioredoxin reductase (TrxR) 1 cytoplasmic isoform 3, glucose-6-phosphate 1-dehydrogenase isoform a, Hsp105, vimentin, and tumor necrosis factor a-induced protein (TNAP)2 expression. Active hirsutinolides inhibited anchorage-dependent and three-dimensional spheroid growth, survival, and migration of human glioma lines and glioma patients' tumor-derived xenograft cells harboring constitutively active Stat3. Oral gavage delivery of 6 or 22 inhibited human glioma tumor growth in subcutaneous mouse xenografts. The inhibition of Stat3 signaling represents part of the hirsutinolide-mediated mechanisms to induce antitumor effects.

  DOI：

  10.1021/acs.jmedchem.5b00686

文献信息

• [EN] NOVEL SESQUITERPENOID STAT3 INHIBITORS<br/>[FR] NOUVEAUX INHIBITEURS DE STAT3 SESQUITERPÉNOÏDES
  申请人：UNIV HAWAII

  公开号：WO2014205416A1

  公开（公告）日：2014-12-24

  The present disclosure provides a method of purifying pharmaceutical compositions consisting essentially of STAT3 inhibitors from a mixture of compounds, pharmaceutical compositions comprising STAT3 inhibitors used to inhibit STAT3 in tumor cells, and certain pharmaceutically acceptable salts thereof, and methods of use. The present disclosure features, in some embodiments, novel, potent and selective STAT3 inhibitors, including sesquiterpene lactone inhibitors.

  本公开提供了一种从化合物混合物中纯化主要由STAT3抑制剂组成的药物组合物的方法，所述药物组合物包括用于抑制肿瘤细胞中的STAT3的STAT3抑制剂，以及其某些药用可接受的盐，以及使用方法。本公开在某些实施例中具有新颖、强效和选择性的STAT3抑制剂，包括倍半萜内酯抑制剂。
• Hirsutinolide Series Inhibit Stat3 Activity, Alter GCN1, MAP1B, Hsp105, G6PD, Vimentin, TrxR1, and Importin α-2 Expression, and Induce Antitumor Effects against Human Glioma
  作者：Gabriella Miklossy、Ui Joung Youn、Peibin Yue、Mingming Zhang、Chih-Hong Chen、Tyvette S. Hilliard、David Paladino、Yifei Li、Justin Choi、Jann N. Sarkaria、Joel K. Kawakami、Supakit Wongwiwatthananukit、Yuan Chen、Dianqing Sun、Leng Chee Chang、James Turkson

  DOI：10.1021/acs.jmedchem.5b00686

  日期：2015.10.8

  We report that hirsutinolide series, 6, 7, 10, 11, 20, and 22, and the semisynthetic analogues, 30, 31, 33, and 36, inhibit constitutively active signal transducer and activator of transcription (Stat)3 and malignant glioma phenotype. A position 13 lipophilic ester group is required for activity. Molecular modeling and nuclear magnetic resonance structural analyses reveal direct hirsutinolide:Stat3 binding. One-hour treatment of cells with 6 and 22 also upregulated importin subunit alpha-2 levels and repressed translational activator GCN1, microtubule-associated protein (MAP) 1B, thioredoxin reductase (TrxR) 1 cytoplasmic isoform 3, glucose-6-phosphate 1-dehydrogenase isoform a, Hsp105, vimentin, and tumor necrosis factor a-induced protein (TNAP)2 expression. Active hirsutinolides inhibited anchorage-dependent and three-dimensional spheroid growth, survival, and migration of human glioma lines and glioma patients' tumor-derived xenograft cells harboring constitutively active Stat3. Oral gavage delivery of 6 or 22 inhibited human glioma tumor growth in subcutaneous mouse xenografts. The inhibition of Stat3 signaling represents part of the hirsutinolide-mediated mechanisms to induce antitumor effects.