14-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: 14-hydroxy-parthenolide
• 英文别名: (1S,2S,4R,7Z,11S)-8-(hydroxymethyl)-4-methyl-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: BAURYGOYSLZFPX-NDEJYMQJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  19
• 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：
  59.1
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  14-hydroxy-parthenolide 在 叠氮磷酸二苯酯 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 四氢呋喃 为溶剂， 以68.8%的产率得到
  参考文献：
  名称：

  小白菊内酯-三氮唑化合物，及其在制备治疗癌症的药物中的用途

  摘要：

  本发明提供了式(I)小白菊内酯‑三氮唑化合物，及其在制备治疗癌症的药物中的用途。

  公开号：

  CN110684034A
• 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54%的产率得到14-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

• Chemoenzymatic synthesis and antileukemic activity of novel C9- and C14-functionalized parthenolide analogs
  作者：Vikas Tyagi、Hanan Alwaseem、Kristen M. O’Dwyer、Jessica Ponder、Qi Ying Li、Craig T. Jordan、Rudi Fasan

  DOI：10.1016/j.bmc.2016.06.028

  日期：2016.9

  patient-derived primary AML specimens with improved activity compared to parthenolide, exhibiting LC50 values in the low micromolar range. These studies demonstrate that different O-H functionalization chemistries can be applied to elaborate the parthenolide scaffold and that modifications at the C9 or C14 position can effectively enhance the antileukemic properties of this natural product. The C9-functionalized

  帕特诺尔是一种天然萜烯，具有令人信服的抗癌特性，尤其是在急性髓细胞性白血病（AML）的情况下。在不影响药理学上重要的α-亚甲基-γ-内酯部分的情况下，对该分子进行后期功能化的机会有限，这对天然产物的优化提出了挑战。在这里，我们报告化学酶策略的进一步发展和应用，以提供一系列在脂肪族位置C9和C14上官能化的苯乙内酯的新类似物。这些化合物中的几种经确定能够杀死白血病细胞和患者来源的原发性AML标本，与单酚类相比，具有更高的活性，在低微摩尔范围内显示出LC50值。这些研究表明，可以使用不同的OH官能化化学方法来精制小白菊内酯骨架，并且在C9或C14位置进行修饰可以有效增强该天然产物的抗白血病特性。就抗白血病的能力和对AML相对于健康血细胞的选择性而言，C9-官能化的类似物22a和25b被鉴定为最令人感兴趣的化合物。
• Transannular Cyclization in Cyclodecenes: The Case Study of Melampolides
  作者：Hannes Neukirch、Antonio Guerriero、Michele D’Ambrosio

  DOI：10.1002/ejoc.200300315

  日期：2003.10

  The structures of products formed by electrophilic transannular cyclization (ETC) in medium-ring compounds are affected by several parameters. The melampolides, (cis,trans)-cyclodeca-1(10),5-diene terpenes, undergo ring closure only under Lewis acid conditions. The transannular distance proves to be a key factor. Molecular mechanics calculations suggest that the cis ring junction of products is formed

  中环化合物中亲电环化 (ETC) 形成的产物的结构受几个参数的影响。melampolides，(cis,trans)-cyclodeca-1(10),5-diene terpenes，只有在路易斯酸条件下才会发生闭环。环向距离被证明是一个关键因素。分子力学计算表明产物的顺式环连接是通过较少的构象异构体形成的。ETC 具有化学意义，因为它可能在倍半萜内酯的药理作用中起重要作用。(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
• Design, synthesis, and cytotoxic activities of novel hybrids of parthenolide and thiazolidinedione via click chemistry
  作者：Jie Qiu、Chun-Mao Yuan、Min Wen、Ya-Nan Li、Juan Chen、Jun-You Jian、Lie-Jun Huang、Wei Gu、Yan-Mei Li、Xiao-Jiang Hao

  DOI：10.1080/10286020.2019.1597055

  日期：2020.5.3

  A series of novel parthenolide-thiazolidinedione hybrids have been synthesized via a click chemistry-mediated coupling between parthenolide and thiazolidinedione, and evaluated for their cytotoxic activities. The results indicated that all the hybrids showed moderate cytotoxic effects on human cancer cell lines, including human erythroleukemia cell line (HEL), prostate (PC3), and breast (MDA-MB-231) by MTT assay. In particular, compound VI-6 exhibited the best cytotoxic activities against the MDA-MB-231 cells with IC50 value of 2.07 mu M, which was about eight times more active than that of the original compound (PTL). These interesting results might be used to develop novel lead scaffolds for potential anticancer agents.[GRAPHICS].
• Discovery of Potent Parthenolide-Based Antileukemic Agents Enabled by Late-Stage P450-Mediated C—H Functionalization
  作者：Joshua N. Kolev、Kristen M. O’Dwyer、Craig T. Jordan、Rudi Fasan

  DOI：10.1021/cb400626w

  日期：2014.1.17

  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.
• Melampomagnolide B: A new antileukemic sesquiterpene
  作者：Shama Nasim、ShanShan Pei、Fred K. Hagen、Craig T. Jordan、Peter A Crooks

  DOI：10.1016/j.bmc.2010.12.045

  日期：2011.2

  Melampomagnolide B has been identified as a new antileukemic sesquiterpene. A biotin-conjugated derivative of melampomagnolide B was designed and synthesized in order to elucidate its mechanism of action. A study of the biochemical interactions of the biotin probe suggests that melampomagnolide B derives its remarkable selectivity for leukemic cells over normal hematopoietic cells from its unique ability to exploit biochemical differences between the two cell types. (C) 2011 Elsevier Ltd. All rights reserved.