9(S)-hydroxy-parthenolide

• 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: 9(S)-hydroxy-parthenolide
• 英文别名: 9β-hydroxyparthenolide；9beta-Hydroxyparthenolide；(1S,2S,4R,7E,9S,11S)-9-hydroxy-4,8-dimethyl-12-methylidene-3,14-dioxatricyclo[9.3.0.02,4]tetradec-7-en-13-one
• 化学式: C₁₅H₂₀O₄
• 分子量: 264.321
• InChiKey: RZUCCKARTVHQBW-MPFAERRBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  19
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  59.1
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  9(S)-hydroxy-parthenolide 、 3-(三氟甲基)苯甲酰氯 在 4-二甲氨基吡啶 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 2.0h， 生成 (3aS,5S,9aR,10aS,10bS,E)-6,9a-dimethyl-3-methylene-2-oxo-2,3,3a,4,5,8,9,9a,10a,10b-decahydrooxireno[2',3':9,10]cyclodeca[1,2-b]furan-5-yl 3-(trifluoromethyl)benzoate
  参考文献：
  名称：

  Discovery of Potent Parthenolide-Based Antileukemic Agents Enabled by Late-Stage P450-Mediated C—H Functionalization

  摘要：

  The sesquiterpene lactone parthenolide has recently attracted considerable attention owing to its promising antitumor properties, in particular in the context of stem-cell cancers including leukemia. Yet, the lack of viable synthetic routes for re-elaborating this complex natural product has represented a fundamental obstacle toward further optimization of its pharmacological properties. Here, we demonstrate how this challenge could be addressed via selective, late-stage sp(3) C-H bond functionalization mediated by P450 catalysts with tailored site-selectivity. Taking advantage of our recently introduced tools for high-throughput P450 fingerprinting and fingerprint-driven P450 reactivity prediction, we evolved P450 variants useful for carrying out the highly regioselective hydroxylation of two aliphatic sites (C9 and C14) in parthenolide carbocyclic backbone. By chemoenzymatic synthesis, a panel of novel C9- and C14-modified parthenolide analogs were generated in order to gain initial structure-activity insights on these previously inaccessible sites of the molecule. Notably, some of these compounds were found to possess significantly improved antileukemic potency against primary acute myeloid leukemia cells, while exhibiting low toxicity against normal mature and progenitor hematopoietic cells. By identifying two 'hot spots' for improving the anticancer properties of parthenolide, this study highlights the potential of P450-mediated C-H functionalization as an enabling, new strategy for the late-stage manipulation of bioactive natural product scaffolds.

  DOI：

  10.1021/cb400626w
• 作为产物：
  描述：

  parthenolide 在 sodium phosphite 、 phosphite dehydrogenase 、 nicotinamide adenine dinucleotide phosphate 作用下， 以 aq. phosphate buffer 为溶剂， 反应 14.0h， 以44%的产率得到9(S)-hydroxy-parthenolide
  参考文献：
  名称：

  通过P450介导的化学酶促合成产生的小白菊内酯类似物的抗癌活性分析

  摘要：

  最近发现植物来源的倍半萜内酯单酚（PTL）具有有希望的抗癌活性，但是通过可用的化学方法证明了对这种天然产物支架进行精制以优化其药理性能已证明是具有挑战性的。在这项工作中，PTL催化PTL中C9和C14位置的C–H羟基羟基化反应与氨基甲酰化化学反应生成一组基于氨基甲酸酯的新型PTL类似物（“ parthenologs”）。这些化合物，以及通过O–H酰化，烷基化和金属催化的卡宾插入获得的一系列其他C9和C14功能化的单性同系物，针对其对多种人类癌细胞系的细胞毒性进行了分析。这些研究导致发现了几种单亲同源物，与亲本分子相比，它们具有显着改善的抗癌活性（2-14倍）。最有趣的是，两个具有高细胞毒性的PTL类似物（LC50  〜1-3μM）对T细胞白血病（的Jurkat），套细胞淋巴瘤（JEKO-1）和腺癌（HeLa细胞）细胞以及具有有效活性（LC氨基甲酸酯衍生物50  = 0.6μM）对成神经细胞

  DOI：

  10.1016/j.bmc.2017.08.009

文献信息

• Synthesis and biological evaluation of 9α- and 9β-hydroxyamino-parthenolides as novel anticancer agents
  作者：Mohamed Moumou、Abderrahman El Bouakher、Hassan Allouchi、Ahmed El Hakmaoui、Ahmed Benharref、Véronique Mathieu、Gérald Guillaumet、Mohamed Akssira

  DOI：10.1016/j.bmcl.2014.06.019

  日期：2014.8

  A series of 9α-hydroxyamino-parthenolides 3–10, 9β-hydroxyamino-parthenolides 11–13 and 9α-hydroxy-1β,10α-epoxyamino-parthenolides 15–19 were efficiently synthesized starting from 9α-hydroxyparthenolide 1 and 9β-hydroxyparthenolide 2, which were isolated from Anvillea radiata. Compounds 1–13 and 15–19 were evaluated for their in vitro anticancer activity by the MTT colorimetric assay against one murine

  一系列9α羟氨基parthenolides 3 - 10，9β羟氨基parthenolides 11 - 13和9α羟基1β，10α-epoxyamino-parthenolides 15 - 19被有效地合成从9α-hydroxyparthenolide开始1和9β-hydroxyparthenolide 2，从Anvillea辐射中分离出来的。化合物1 – 13和15 – 19通过MTT比色测定法对一种小鼠和六种人类癌细胞系评估它们的体外抗癌活性。这项工作提供了有关抗癌活性的结构要求的新细节。
• Synthetic Modification of 9α- and 9β-Hydroxyparthenolide by Heck or Acylation Reactions and Evaluation of Cytotoxic Activities
  作者：Abderrahman El Bouakher、Badr Jismy、Hassan Allouchi、Eric Duverger、Latifa Barkaoui、Ahmed El Hakmaoui、Richard Daniellou、Gérald Guillaumet、Mohamed Akssira

  DOI：10.1055/s-0042-119864

  日期：——

  anticancer activity of parthenolides and their derivatives, a series of new substituted parthenolides was efficiently synthesized. Structural modifications were performed at the C-9 and C-13 positions of 9α- and 9β-hydroxyparthenolide, which were isolated from the aerial parts of Anvillea radiata. Twenty-one derivatives were synthesized and evaluated for their in vitro cytotoxic activity against HS-683,

  受广泛报道的小白菊内酯及其衍生物的抗癌活性的影响，有效合成了一系列新的取代的小白菊内酯。结构修饰是在9α-和9β-羟基小白菊的C-9和C-13位置上进行的，这些位置是从辐射小牛的地上部分中分离出来的。合成了二十一种衍生物，并使用MTT比色测定法评估了它们对HS-683，SK-MEL-28，A549和MCF-7人癌细胞系的体外细胞毒活性。在这些衍生物中，有七个与5-氟尿嘧啶和依托泊苷相比，对四种测试细胞系表现出优异的活性，IC50值在1.1至9.4 µM之间。
• Synthesis of novel spiro-pyrazole and spiro-isoxazoline derivatives of 9α- and 9β-hydroxyparthenolide
  作者：Fatima Outahar、Mohamed Moumou、Abdellah Hannioui、El Mostapha Rakib、Lahcen El Ammari、Mohamed Saadi、Mohamed Akssira

  DOI：10.1016/j.tetlet.2020.152409

  日期：2020.10

  A series of novel spiropyrazoles and spiroisoxazolines was efficiently synthesized. Structural modifications were performed at the C-9 and C-13 positions of 9α- and 9β-hydroxyparthenolide, which were isolated from the aerial parts of Anvillea radiata. The structures and stereochemistry of the cycloadducts were fully established by spectroscopic methods including X-ray diffraction data.

  高效合成了一系列新型螺吡唑和螺异恶唑啉。结构修饰是在9α-和9β-羟基单酚的C-9和C-13位置进行的，这些位置是从辐射小ville的空中部分分离出来的。通过包括X射线衍射数据在内的光谱方法可以完全确定环加合物的结构和立体化学。
• Hepatoprotective and cytotoxic activities of Anvillea garcinii and isolation of four new secondary metabolites
  作者：Shagufta Perveen、Areej Mohammad Al-Taweel、Hasan Soliman Yusufoglu、Ghada Ahmed Fawzy、Ahmed Foudah、Maged Saad Abdel-Kader

  DOI：10.1007/s11418-017-1118-1

  日期：2018.1

  is a medicinal plant traditionally used for the treatment of dysentery, gastrointestinal troubles, hepatitis, lung disease, colds, digestive problems and pulmonary affections and in liver diseases. Four new sesquiterpene lactones, garcinamines A–D, along with seven known compounds, were isolated from the leaves of A. garcinii. This is the first report of the isolation of amino acid analogues of parthenolide-type

  Anvillea garcinii是传统上用于治疗痢疾，胃肠道疾病，肝炎，肺部疾病，感冒，消化问题和肺部疾病以及肝病的药用植物。从藤黄曲霉的叶子中分离出四种新的倍半萜内酯，藤黄胺A–D和七种已知化合物。这是从菊科（Asteraceae）分离白菊内酯型倍半萜内酯的氨基酸类似物的首次报道。叶子的总乙醇提取物以及氯仿和正己烷使用四氯化碳肝毒性模型测试了丁醇的肝保护作用。在所有血清和组织参数方面，剂量为400 mg / kg的氯仿组分均显示出与水飞蓟素相当的显着的肝保护作用。评估了所有提取物和化合物对五种人类癌细胞系的细胞毒性：MCF-7，HCT-116，HepG2，Hela和A-549。结果表明，在氯仿和Ñ丁醇级分和化合物3，4，7和8显示显著细胞毒性活性对这些细胞系。
• 10.1021/cb400626
  作者：Kolev, Joshua N.、O'Dwyer, Kristen M.、Jordan, Craig T.、Fasan, Rudi

  DOI：10.1021/cb400626

  日期：——