(3aS,9R,9aS,9bS)-6,9-dimethyl-3-methylene-2-oxo-2,3,3a,4,5,7,8,9,9a,9b-decahydroazuleno[4,5-b]furan-9-yl hex-5-ynoate

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: (3aS,9R,9aS,9bS)-6,9-dimethyl-3-methylene-2-oxo-2,3,3a,4,5,7,8,9,9a,9b-decahydroazuleno[4,5-b]furan-9-yl hex-5-ynoate
• 英文别名: [(3aS,9R,9aS,9bS)-6,9-dimethyl-3-methylidene-2-oxo-4,5,7,8,9a,9b-hexahydro-3aH-azuleno[8,7-b]furan-9-yl] hex-5-ynoate
• 化学式: C₂₁H₂₆O₄
• 分子量: 342.435
• InChiKey: VFMSFGFTTGGMGZ-MCNSAMFCSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  52.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (3aS,9R,9aS,9bS)-6,9-dimethyl-3-methylene-2-oxo-2,3,3a,4,5,7,8,9,9a,9b-decahydroazuleno[4,5-b]furan-9-yl hex-5-ynoate 在 potassium carbonate 、 copper(II) sulfate 、 sodium ascorbate 作用下， 以 甲醇 、 二氯甲烷 、 水 、 叔丁醇 为溶剂， 生成
  参考文献：
  名称：

  ACT001 inhibited CD133 transcription by targeting and inducing Olig2 ubiquitination degradation

  摘要：

  摘要 肺癌是最致命的恶性肿瘤，具有侵袭性强、预后差等特点。迄今为止，肺癌患者的五年生存率仍未得到改善，给人类健康带来严峻挑战。肺癌干细胞（LCSCs）是癌症发生、发展、复发和耐药的根源。因此，有效的抗癌药物和能特异性消除 LCSCs 的分子机制是药物设计的迫切需要。本文中，我们发现Olig2在临床肺癌组织中过表达，并作为转录因子通过调控CD133基因转录来调控癌症干性。结果表明，Olig2可能是抗肺癌干细胞治疗的一个有前景的靶点，靶向Olig2的新药可能会取得很好的临床效果。此外，我们还验证了一种胍内倍半萜内酯 ACT001，它通过直接与 Olig2 蛋白结合，诱导 Olig2 泛素化降解并抑制 CD133 基因转录，从而抑制肿瘤干性。所有这些结果表明，Olig2可能是抗肺癌干细胞治疗的一个很好的药物靶点，为ACT001在临床上进一步应用于肺癌治疗奠定了基础。

  DOI：

  10.1038/s41389-023-00462-6
• 作为产物：
  描述：

  5-己炔酸 在 吡啶 、 4-二甲氨基吡啶 、 草酰氯 作用下， 以 二氯甲烷 为溶剂， 反应 1.5h， 生成 (3aS,9R,9aS,9bS)-6,9-dimethyl-3-methylene-2-oxo-2,3,3a,4,5,7,8,9,9a,9b-decahydroazuleno[4,5-b]furan-9-yl hex-5-ynoate
  参考文献：
  名称：

  Natural Product Micheliolide (MCL) Irreversibly Activates Pyruvate Kinase M2 and Suppresses Leukemia

  摘要：

  Metabolic reprogramming of cancer cells is essential for tumorigenesis in which pyruvate kinase M2 (P1342), the low activity isoform of pyruvate kinase, plays a critical role. Herein, we describe the identification of a nature-product-derived micheliolide (MCL) that selectively activates PKM2 through the covalent binding at residue cysteine424 (C424), which is not contained in PKM1. This interaction promotes more tetramer formation, inhibits the lysine433 (K433) acetylation, and influences the translocation of PKM2 into the nucleus. In addition, the pro-drug dimethylaminomicheliolide (DMAMCL) with similar properties as MCL significantly suppresses the growth of leukemia cells and tumorigenesis in a zebrafish xenograft model. Cell-based assay with knock down PKM2 expression verifies that the effects of MCL are dependent on PKM2 expression. DMAMCL is currently in clinical trials in Australia. Our discovery may provide a valuable pharmacological mechanism for clinical treatment and benefit the development of new anticancer agents.

  DOI：

  10.1021/acs.jmedchem.8b00241

文献信息

• USES OF SESQUITERPENE LACTONE COMPOUNDS AND THEIR DERIVATIVES IN DRUGS PREPARATION
  申请人：ACCENDATECH

  公开号：US20160367525A1

  公开（公告）日：2016-12-22

  The present invention relates to the uses of sesquiterpene lactone compounds and their derivatives in preparing drugs. It belongs to the field of drug technology, specifically relates to the uses of the compounds of Formula (I) in preparing the drugs, especially the uses in preparing the drugs to treat rheumatoid arthritis and treat cancers through inhibiting cancer stem cells.

  本发明涉及倍半萜内酯化合物及其衍生物在制备药物中的用途。它属于药物技术领域，具体涉及在制备药物中使用式(I)化合物，特别是在制备用于治疗类风湿关节炎和通过抑制癌干细胞治疗癌症的药物中的用途。
• 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。
• Synthesis of Micheliolide Derivatives and Their Activities against AML Progenitor Cells
  作者：Wei-Wei Ma、Qian-Qian Shi、Ya-Hui Ding、Jing Long、Quan Zhang、Yue Chen

  DOI：10.3390/molecules18055980

  日期：——

  Micheliolide (MCL) derivatives with etherification or esterification of the hydroxyl group at the C4 position were synthesized and evaluated for their activities against different acute myelogenous leukemia (AML) cell lines. These derivatives demonstrated comparable activities against AML cell lines HL-60 and doxorubicin resistant cell line HL-60/A. As to multi-drug resistant AML progenitor cells KG-1a, MCL and some of its derivatives maintained significant activities, and only 1.1–2.7 fold activity reductions were observed when compared with the activities against HL-60, while doxorubicin showed 20-fold activity reduction. Our study demonstrated that the C4 hydroxyl group of MCL might not only be a suitable position for structural modifications, but also be a starting point for the design of appropriate molecular probes to explore the specific targets in the progenitor cell line KG-1a.

  合成了在C4位点的羟基经过醚化或酯化的Micheliolide（MCL）衍生物，并评估其对不同急性髓性白血病（AML）细胞系的活性。这些衍生物对AML细胞系HL-60及多柔比星耐药细胞系HL-60/A表现出了相当的活性。至于多药耐药AML祖细胞KG-1a，MCL及其某些衍生物维持了显著的活性，与对HL-60的活性相比，仅观察到1.1-2.7倍的活性减少，而多柔比星则显示出20倍的活性减少。我们的研究表明，MCL的C4羟基不仅是结构修饰的合适位置，也是设计合适分子探针以探索KG-1a祖细胞系中特定靶标的起点。
• Natural Product Micheliolide (MCL) Irreversibly Activates Pyruvate Kinase M2 and Suppresses Leukemia
  作者：Jing Li、Shanshan Li、Jianshuang Guo、Qiuying Li、Jing Long、Cheng Ma、Yahui Ding、Chunli Yan、Liangwei Li、Zhigang Wu、He Zhu、Keqin Kathy Li、Liuqing Wen、Quan Zhang、Qingqing Xue、Caili Zhao、Ning Liu、Ivaylo Ivanov、Ming Luo、Rimo Xi、Haibo Long、Peng George Wang、Yue Chen

  DOI：10.1021/acs.jmedchem.8b00241

  日期：2018.5.10

  Metabolic reprogramming of cancer cells is essential for tumorigenesis in which pyruvate kinase M2 (P1342), the low activity isoform of pyruvate kinase, plays a critical role. Herein, we describe the identification of a nature-product-derived micheliolide (MCL) that selectively activates PKM2 through the covalent binding at residue cysteine424 (C424), which is not contained in PKM1. This interaction promotes more tetramer formation, inhibits the lysine433 (K433) acetylation, and influences the translocation of PKM2 into the nucleus. In addition, the pro-drug dimethylaminomicheliolide (DMAMCL) with similar properties as MCL significantly suppresses the growth of leukemia cells and tumorigenesis in a zebrafish xenograft model. Cell-based assay with knock down PKM2 expression verifies that the effects of MCL are dependent on PKM2 expression. DMAMCL is currently in clinical trials in Australia. Our discovery may provide a valuable pharmacological mechanism for clinical treatment and benefit the development of new anticancer agents.
• ACT001 inhibited CD133 transcription by targeting and inducing Olig2 ubiquitination degradation
  作者：Huiting Deng、Hailin Liu、Guoyue Yang、Dandan Wang、Ying Luo、Chenglong Li、Zhenchang Qi、Zhili Liu、Peng Wang、Yanfang Jia、Yingtang Gao、Yahui Ding

  DOI：10.1038/s41389-023-00462-6

  日期：——

  Lung cancer is the most lethal malignancies with high aggressive and poor prognosis. Until now, the five-year survival rate has not been improved which brings serious challenge to human health. Lung cancer stem cells (LCSCs) serve as the root of cancer occurrence, progression, recurrence, and drug resistance. Therefore, effective anti-cancer agents and molecular mechanisms which could specifically eliminate LCSCs are urgently needed for drug design. In this article, we discovered Olig2 was overexpressed in clinical lung cancer tissues and acted as a transcription factor to regulate cancer stemness by regulating CD133 gene transcription. The results suggested Olig2 could be a promising target in anti-LCSCs therapy and new drugs targeted Olig2 may exhibit excellent clinical results. Furthermore, we verified ACT001, a guaianolide sesquiterpene lactone in phase II clinical trial with excellent glioma remission, inhibited cancer stemness by directly binding to Olig2 protein, inducing Olig2 ubiquitination degradation and inhibiting CD133 gene transcription. All these results suggested that Olig2 could be an excellent druggable target in anti-LCSCs therapy and lay a foundation for the further application of ACT001 in the treatment of lung cancer in clinical.

  摘要 肺癌是最致命的恶性肿瘤，具有侵袭性强、预后差等特点。迄今为止，肺癌患者的五年生存率仍未得到改善，给人类健康带来严峻挑战。肺癌干细胞（LCSCs）是癌症发生、发展、复发和耐药的根源。因此，有效的抗癌药物和能特异性消除 LCSCs 的分子机制是药物设计的迫切需要。本文中，我们发现Olig2在临床肺癌组织中过表达，并作为转录因子通过调控CD133基因转录来调控癌症干性。结果表明，Olig2可能是抗肺癌干细胞治疗的一个有前景的靶点，靶向Olig2的新药可能会取得很好的临床效果。此外，我们还验证了一种胍内倍半萜内酯 ACT001，它通过直接与 Olig2 蛋白结合，诱导 Olig2 泛素化降解并抑制 CD133 基因转录，从而抑制肿瘤干性。所有这些结果表明，Olig2可能是抗肺癌干细胞治疗的一个很好的药物靶点，为ACT001在临床上进一步应用于肺癌治疗奠定了基础。