4-hydroxy-3, 4-seco-olean-12-en-28-oic acid 3, 4 lactone

• 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: 4-hydroxy-3, 4-seco-olean-12-en-28-oic acid 3, 4 lactone
• 英文别名: olean-12-en-28-carboxy-3-oic acid ε-lactone；(1R,2S,5S,10S,14R,15R,21R)-1,2,8,8,15,20,20-heptamethyl-18-oxo-19-oxapentacyclo[12.9.0.02,11.05,10.015,21]tricos-11-ene-5-carboxylic acid
• 化学式: C₃₀H₄₆O₄
• 分子量: 470.693
• InChiKey: IVNWEUTZHBKHJJ-FUAOEXFOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.8
• 重原子数：
  34
• 可旋转键数：
  1
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.87
• 拓扑面积：
  63.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-hydroxy-3, 4-seco-olean-12-en-28-oic acid 3, 4 lactone 在 草酰氯 作用下， 以 二氯甲烷 为溶剂， 反应 1.5h， 生成
  参考文献：
  名称：

  Triterpenoid Hydroxamates as HIF Prolyl Hydrolase Inhibitors

  摘要：

  Pentacyclic triterpenoid acids (PCTTAs) are pleiotropic agents that target many macromolecular endpoints with low to moderate affinity. To explore the biological space associated with PCTTAs, we have investigated the carboxylate-to-hydroxamate transformation, discovering that it de-emphasizes affinity for the transcription factors targeted by the natural compounds (NF-kappa B, STAT3, Nrf2, TGRS) and selectively induces inhibitory activity on HIF prolyl hydrolases (PHDs). Activity was reversible, isoform-selective, dependent on the hydroxamate location, and negligible when this group was replaced by other chelating elements or O-alkylated. The hydroxamate of betulinic acid (Sb) was selected for further studies, and evaluation of its effect on HIF-la expression under normal and hypoxic conditions qualified it as a promising lead structure for the discovery of new candidates in the realm of neuroprotection.

  DOI：

  10.1021/acs.jnatprod.8b00514
• 作为产物：
  描述：

  齐墩果酸 在 Jones reagent 、 10% palladium on activated carbon 、 氢气 、 lithium carbonate 、 potassium carbonate 、 间氯过氧苯甲酸 作用下， 以 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 20.0 ℃ 、800.01 kPa 条件下， 反应 32.0h， 生成 4-hydroxy-3, 4-seco-olean-12-en-28-oic acid 3, 4 lactone
  参考文献：
  名称：

  齐墩果酸衍生物作为蛋白质酪氨酸磷酸酶1B抑制剂的合成及生物学评价

  摘要：

  蛋白酪氨酸磷酸酶1B（PTP1B）是胰岛素信号传导过程中的负调节剂，是糖尿病和肥胖症的有希望的药物靶标。合成齐墩果酸的衍生物并评价为PTP1B抑制剂。几种衍生物对PTP1B表现出中等至良好的抑制活性，其中25f表现出最有希望的抑制作用（IC 50 = 3.12μM）。这些衍生物的结构活性关系分析表明，A环和12-烯部分的完整性在保留PTP1B酶抑制活性中很重要。此外，亲水和酸性基团以及齐墩烯与酸部分之间的距离与PTP1B抑制活性有关。25f的可能绑定模式 通过分子对接模拟进行了探索。

  DOI：

  10.1021/np100064m

文献信息

• Synthesis and Biological Evaluation of Oleanolic Acid Derivatives As Inhibitors of Protein Tyrosine Phosphatase 1B
  作者：Shan Qian、Haijiao Li、Yin Chen、Weiyu Zhang、Shengyong Yang、Yong Wu

  DOI：10.1021/np100064m

  日期：2010.11.29

  Protein tyrosine phosphatase 1B (PTP1B) is a negative regulator in the process of insulin signaling and a promising drug target for diabetes and obesity. Derivatives of oleanolic acid were synthesized and evaluated as PTP1B inhibitors. Several derivatives exhibited moderate to good inhibitory activities against PTP1B, with 25f displaying the most promising inhibition (IC50 = 3.12 μM). Structure−activity

  蛋白酪氨酸磷酸酶1B（PTP1B）是胰岛素信号传导过程中的负调节剂，是糖尿病和肥胖症的有希望的药物靶标。合成齐墩果酸的衍生物并评价为PTP1B抑制剂。几种衍生物对PTP1B表现出中等至良好的抑制活性，其中25f表现出最有希望的抑制作用（IC 50 = 3.12μM）。这些衍生物的结构活性关系分析表明，A环和12-烯部分的完整性在保留PTP1B酶抑制活性中很重要。此外，亲水和酸性基团以及齐墩烯与酸部分之间的距离与PTP1B抑制活性有关。25f的可能绑定模式 通过分子对接模拟进行了探索。
• Ring-A cleavage of 3-oxo-olean-12-en-28-oic acid by the fungus Chaetomium longirostre
  作者：Noboru Shirane、Yutaka Hashimoto、Kazuo Ueda、Hideyuki Takenaka、Kenji Katoh

  DOI：10.1016/0031-9422(96)00266-x

  日期：1996.9

  3-Oxo-olean-12-en-28-oic acid was transformed by the filamentous fungus Chaetomium longirostre into 3,4-seco-olean-12-en-4-ol-3,28-dioic acid and the 21 beta-hydroxylated compound. A cell-free preparation derived from the fungus converted 3-oxo-olean-12-en-28-oic acid into 3,4-seco-olean-12-en-4-ol-3,28-dioic acid. The ring-A cleavage activity was detected in the soluble fraction of the cell-free preparation and showed a requirement for NADPH. Copyright (C) 1996 Elsevier Science Ltd
• A-<i>seco</i>-Oleane-Type Triterpene Acids from<i>Ligularia intermedia</i>
  作者：Bin Ma、Yan-Ping Shi、Zhong-Jian Jia

  DOI：10.1055/s-2006-957773

  日期：1997.12

  From the roots of Ligularia intermedia, two new naturally occurring 3,4-seco-oleanolic triterpene acids were isolated. Their structures were elucidated as A-homo-3a-oxa-olean-12-en-3-one-28-oic acid (1) and 3,4-seco-olean-12-en-4-ol-3,28-dioic acid (2) by spectroscopic methods and chemical transformations. In addition, six known compounds (5-10) were also obtained from this plant.
• Triterpenoid Hydroxamates as HIF Prolyl Hydrolase Inhibitors
  作者：Alberto Minassi、Federica Rogati、Cristina Cruz、M. Eugenia Prados、Nuria Galera、Carla Jinénez、Giovanni Appendino、M. Luz Bellido、Marco A Calzado、Diego Caprioglio、Eduardo Muñoz

  DOI：10.1021/acs.jnatprod.8b00514

  日期：2018.10.26

  Pentacyclic triterpenoid acids (PCTTAs) are pleiotropic agents that target many macromolecular endpoints with low to moderate affinity. To explore the biological space associated with PCTTAs, we have investigated the carboxylate-to-hydroxamate transformation, discovering that it de-emphasizes affinity for the transcription factors targeted by the natural compounds (NF-kappa B, STAT3, Nrf2, TGRS) and selectively induces inhibitory activity on HIF prolyl hydrolases (PHDs). Activity was reversible, isoform-selective, dependent on the hydroxamate location, and negligible when this group was replaced by other chelating elements or O-alkylated. The hydroxamate of betulinic acid (Sb) was selected for further studies, and evaluation of its effect on HIF-la expression under normal and hypoxic conditions qualified it as a promising lead structure for the discovery of new candidates in the realm of neuroprotection.
• Design, synthesis and biological evaluation of seco-A-pentacyclic triterpenoids-3,4-lactone as potent non-nucleoside HBV inhibitors
  作者：Zhijian Li、Qingxi Min、Haoji Huang、Ruixuan Liu、Yongyan Zhu、Quanhong Zhu

  DOI：10.1016/j.bmcl.2018.03.076

  日期：2018.5

  A series of seco-A-pentacyclic triterpenoids-3,4-lactone were synthesized and the anti-HBV activities were evaluated in vitro. Several compounds inhibited the secretion of HBV antigen and the replication of HBV DNA in micromolar level. Compounds D7 and D10, seco-A-oleanane-3,4-lactone, suppressed the HBeAg secretion with IC50 values of 0.14 mu M and 0.86 mu M respectively, and the inhibitory activities were also confirmed by detecting the fluorescence intensity of FITC-labeled monoclonal mouse HBeAg antibody via flow cytometry. Compounds D7 and D10 as well as B4, ring-A cleaved 3,30-dioic acid, also displayed remarkable inhibition on both HBV DNA replication at the concentration of 25 mu M and HBV cccDNA (covalently closed circularDNA) replication with IC50 values of 33.5 mu M, 32.7 mu M and 12.3 mu M respectively. (C) 2018 Elsevier Ltd. All rights reserved.