(-)-(3aS,6R,6aR,9R,9aS,9bS)-decahydro-9-hydroxy-6-methoxy-6,9-dimethyl-3-methyleneazuleno[4,5-b]furan-2(3H)-one

• 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: (-)-(3aS,6R,6aR,9R,9aS,9bS)-decahydro-9-hydroxy-6-methoxy-6,9-dimethyl-3-methyleneazuleno[4,5-b]furan-2(3H)-one
• 英文别名: (3aS,6R,6aR,9R,9aS,9bS)-9-hydroxy-6-methoxy-6,9-dimethyl-3-methylenedecahydroazuleno[4,5-b]furan-2(3H)-one；(3aS,6R,6aR,9R,9aS,9bS)-9-hydroxy-6-methoxy-6,9-dimethyl-3-methylidene-3a,4,5,6a,7,8,9a,9b-octahydroazuleno[4,5-b]furan-2-one
• 化学式: C₁₆H₂₄O₄
• 分子量: 280.364
• InChiKey: NADODSHYBZXLJH-LQTRTAQESA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  20
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  55.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  二甲胺 、 (-)-(3aS,6R,6aR,9R,9aS,9bS)-decahydro-9-hydroxy-6-methoxy-6,9-dimethyl-3-methyleneazuleno[4,5-b]furan-2(3H)-one 在 potassium carbonate 作用下， 以 乙醇 为溶剂， 反应 16.0h， 以89%的产率得到(3R,3aS,6R,6aR,9R,9aS,9bS)-3-((dimethylamino)methyl)-9-hydroxy-6-methoxy-6,9-dimethyldecahydroazuleno[4,5-b]furan-2(3H)-one
  参考文献：
  名称：

  Aniline-containing derivatives of parthenolide: Synthesis and anti-chronic lymphocytic leukaemia activity

  摘要：

  Parthenolide exhibits anti-leukaemia activity, whilst its synthetic modification to impart improve drug-like properties, including 1,4-conjugate addition of primary and secondary amines, have previously been used, 1,4-addition of aniline derivatives to parthenolide has not been fully explored. A protocol for such additions to parthenolide is outlined herein. Reaction conditions were determined using tulipane as a model Michael acceptor. Subsequently, aniline-containing parthenolide derivatives were prepared under the optimised conditions and single crystal X-ray diffraction structures were resolved for three of the compounds synthesised. The synthesised derivatives, along with compounds resulting from a side reaction, were tested for their in vitro anti-leukaemia activity using the chronic lymphocytic leukaemia (CLL) MEC1 cell line. Computational studies with the 2RAM protein structure suggested that the activity of the derivatives was independent of their in silico ability to dock with the Cys38 residue of NF-kappa B. Crown Copyright (C) 2020 Published by Elsevier Ltd.

  DOI：

  10.1016/j.tet.2020.131631
• 作为产物：
  描述：

  dimethylamino-parthenolide fumarate 在 对甲苯磺酸 作用下， 以 aq. buffer 为溶剂， 反应 12.0h， 生成 (-)-(3aS,6R,6aR,9R,9aS,9bS)-decahydro-9-hydroxy-6-methoxy-6,9-dimethyl-3-methyleneazuleno[4,5-b]furan-2(3H)-one
  参考文献：
  名称：

  Guaianolide Sesquiterpene Lactones, a Source To Discover Agents That Selectively Inhibit Acute Myelogenous Leukemia Stem and Progenitor Cells

  摘要：

  Small molecules that can selectively target cancer stem cells (CSCs) remain rare currently and exhibit no common structural features. Here we report a series of guaianolide sesquiterpene lactones (GSLs) and their derivatives that can selectively eradicate acute myelogenous leukemia (AML) stem or progenitor cells. Natural GSL compounds arglabin, an anticancer clinical drug, and micheliolide (MCL), are able to reduce the proportion of AML stem cells (CD34(+)CD38(-)) in primary AML cells. Targeting of AML stem cells is further confirmed by a sharp reduction of colony-forming units of primary AML cells upon MCL treatment. Moreover, DMAMCL, the dimethylamino Michael adduct of MCL, slowly releases MCL in plasma and in vivo and demonstrates remarkable therapeutic efficacy in the nonobese diabetic/severe combined immunodeficiency AML models. These findings indicate that GSL is an ample source for chemical agents against AML stem or progenitor cells and that GSL is potentially highly useful to explore anti-CSC approaches.

  DOI：

  10.1021/jm301064b

文献信息

• 倍半萜内酯类化合物及其衍生物在制备药物中 的用途
  申请人：天津尚德药缘科技股份有限公司

  公开号：CN103417532B

  公开（公告）日：2016-06-01

  本发明涉及倍半萜内酯类化合物及其衍生物在制备药物中的用途，属于药物技术领域，具体涉及式(I)化合物在制备药物中的用途，特别是在制备治疗类风湿性关节炎、通过抑制癌症干细胞用于治疗癌症的药物中的用途。
• Parthenolide and its photochemically synthesized 1(10) Z isomer: chemical reactivity and structure–activity relationship studies in human leucocyte chemotaxis
  作者：Hannes Neukirch、Nicole C Kaneider、Christian J Wiedermann、Antonio Guerriero、Michele D'Ambrosio

  DOI：10.1016/s0968-0896(02)00553-9

  日期：2003.4

  germacrolide into a melampolide. The investigation on their chemical properties allowed us to evaluate the minimum interatomic distance needed for transannular bridging of C(10) ring in germacrolides and to explain the regiochemical selectivity of electrophilic cyclizations. The antiinflammatory activity of parthenolide and its semisynthetic derivatives was evaluated by in vitro chemotaxis assay with human neutrophiles

  目前的研究已经实现了杀菌剂金葡糖胺的光化学转化为聚丙烯酰胺。对它们的化学性质的研究使我们能够评估杀菌棒中C（10）环跨环桥接所需的最小原子间距离，并解释了亲电环化的区域化学选择性。通过对人嗜中性白细胞的体外趋化性分析评估了小白菊内酯及其半合成衍生物的抗炎活性。这些结构-活性关系研究导致了一种新的药效团的假设，并为计算设计的药物提供了有用的信息。
• Sesquiterpene lactone-based pharmaceutical composition for treating gastrointestinal diseases
  申请人：CHO DANG PHARM. CO., LTD.

  公开号：US20150299155A1

  公开（公告）日：2015-10-22

  The present invention relates to a sesquiterpene lactone-based pharmaceutical composition for treating gastrointestinal diseases. More particularly, the present invention relates to a pharmaceutical composition, containing as an active ingredient a sesquiterpene lactone-based derivative derived from parthenolide, for preventing or treating gastritis or gastric ulcers.

  本发明涉及一种基于倍半萜内酯的药物组合物，用于治疗胃肠道疾病。更具体地，本发明涉及一种药物组合物，其包含一种以倍半萜内酯为基础衍生物作为活性成分，用于预防或治疗胃炎或胃溃疡。
• Inhibition of NF-kB and metalloproteinase-9 expression and secretion by parthenolide derivatives
  作者：Mario Dell’Agli、Germana V. Galli、Enrica Bosisio、Michele D’Ambrosio

  DOI：10.1016/j.bmcl.2009.02.080

  日期：2009.4

  Semisynthetic derivatives of parthenolide (1) were tested on NF-kappa B driven transcription and metalloproteinase-9 (MMP-9) expression and secretion. The four membered ring compounds 5 and 6, obtained by acidic treatment of 1, exhibited a higher activity with respect to 1 in all the biological assays. Then an increased ability of the 5 and 6 to inhibit NF-kappa B driven transcription may lead to a down-regulation of MMP-9 expression and secretion. This work provides new details about the structural requisites for NF-kappa B inhibition. (C) 2009 Elsevier Ltd. All rights reserved.
• Aniline-containing derivatives of parthenolide: Synthesis and anti-chronic lymphocytic leukaemia activity
  作者：Alex S. Quy、Xingjian Li、Louise Male、Tatjana Stankovic、Angelo Agathanggelou、John S. Fossey

  DOI：10.1016/j.tet.2020.131631

  日期：2020.11

  Parthenolide exhibits anti-leukaemia activity, whilst its synthetic modification to impart improve drug-like properties, including 1,4-conjugate addition of primary and secondary amines, have previously been used, 1,4-addition of aniline derivatives to parthenolide has not been fully explored. A protocol for such additions to parthenolide is outlined herein. Reaction conditions were determined using tulipane as a model Michael acceptor. Subsequently, aniline-containing parthenolide derivatives were prepared under the optimised conditions and single crystal X-ray diffraction structures were resolved for three of the compounds synthesised. The synthesised derivatives, along with compounds resulting from a side reaction, were tested for their in vitro anti-leukaemia activity using the chronic lymphocytic leukaemia (CLL) MEC1 cell line. Computational studies with the 2RAM protein structure suggested that the activity of the derivatives was independent of their in silico ability to dock with the Cys38 residue of NF-kappa B. Crown Copyright (C) 2020 Published by Elsevier Ltd.