(14S)-14β-(hydroxymethyl)epitriptolide | 1060759-62-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氧杂环己烷
• 英文名称: (14S)-14β-(hydroxymethyl)epitriptolide
• 英文别名: (14S)-14beta-Hydroxymethylepitriptolide；(1S,2S,4S,5S,7S,8S,9R,11S,13S)-8-hydroxy-8-(hydroxymethyl)-1-methyl-7-propan-2-yl-3,6,10,16-tetraoxaheptacyclo[11.7.0.02,4.02,9.05,7.09,11.014,18]icos-14(18)-en-17-one
• CAS: 1060759-62-7
• 化学式: C₂₁H₂₆O₇
• 分子量: 390.433
• InChiKey: JRLMORJQWUCKFI-XESGGTJHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.6
• 重原子数：
  28
• 可旋转键数：
  2
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.86
• 拓扑面积：
  104
• 氢给体数：
  2
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  (14S)-14β-(hydroxymethyl)epitriptolide 在 2,2,6,6-tetramethyl-piperidine-N-oxyl 、 三氯异氰尿酸 、 三乙酰氧基硼氢化钠 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 生成 (14S)-14β-(1-methyl-1H-indazol-5-ylamino)methylepitriptolide
  参考文献：
  名称：

  Design, synthesis and anticancer activity evaluation of novel C14 heterocycle substituted epi-triptolide

  摘要：

  Two series of novel C14 heterocycle substituted epi-triptolide derivatives as potential anticancer agents were synthesized and tested for their cytotoxicity against SKOV-3 and PC-3 tumor cell lines. The introduction of C14 beta-aryl heterocycle aminomethyl substituent to the leading compound was found to be an effective modification method to retain the potent anticancer activity. Meanwhile, the series of epitriptolide derivatives (21-40) with C14 alpha-hydroxyl group, still retained the natural product's cytotoxicity. This is apparently challenges the classical structure activity relationship of triptolide that considers the C14 beta-hydroxyl group to be essential for its anticancer activity. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.11.044
• 作为产物：
  描述：

  雷公藤甲素 在 乙酸酐 、 magnesium 、 溶剂黄146 作用下， 以 四氢呋喃 、 1,2-二溴乙烷 为溶剂， 反应 4.75h， 生成 (14S)-14β-(hydroxymethyl)epitriptolide
  参考文献：
  名称：

  天然雷公藤甲素D环的设计，合成及构效关系研究

  摘要：

  雷公藤甲素是从雷公藤中分离出的二萜三环氧化物天然产物钩F，传统中草药。雷公藤内酯已被证明具有抗肿瘤，抗炎，免疫抑制和抗生育活性。较早的报道表明，五元不饱和内酯环（D环）对于有效的细胞毒性至关重要，但是据我们所知，尚未报道系统的结构-活性关系研究。在这里，针对人类卵巢癌（SKOV-3）和前列腺癌（PC-3）癌细胞系设计，合成和评估了四种类型的D环修饰的雷公藤内酯类似物。结果表明D环对于效力是必不可少的，但是它可以被修饰，例如被修饰为C18氢键受体和/或供体呋喃环类似物，而不会完全丧失细胞毒性。有趣的是，对C19类似物关键序列的评估表明，该位点对极性非常敏感。总之，这些结果将指导这种天然产物铅化合物的进一步优化，以开发有效且可能在临床上有用的雷公藤内酯类似物。

  DOI：

  10.1002/cmdc.201300409

文献信息

• Selective Antitumor Effect and Lower Toxicity of Mitochondrion-Targeting Derivatization of Triptolide
  作者：Wenlan Xing、Guoliang Liu、Yue Zhang、Tao Zhang、Hongxiang Lou、Peihong Fan

  DOI：10.1021/acs.jmedchem.3c01508

  日期：2024.1.25

  selected as targeting carriers for structural modification of triptolide. The derivatives bearing F16 generally retained most antitumor activities, overcame its inhibition plateau phenomena, and enhanced its selective antitumor effect in lung cancer. The representative derivative F9 could accumulate in the mitochondria of NCI-H1975 cells, inducing apoptosis and a dose-dependent increase in intracellular reactive

  雷公藤甲素具有显着的抗肿瘤活性，但其毒性限制了其临床应用。由于肿瘤细胞中线粒体膜电位（MMP）高于正常细胞，线粒体靶向策略显示出选择性抗肿瘤作用的优势，因此亲脂性阳离子三苯基膦和E -4-(1 H -吲哚-3-基乙烯基) - 选择N-甲基碘化吡啶(F16)作为雷公藤内酯醇结构修饰的靶向载体。 F16的衍生物一般保留了大部分抗肿瘤活性，克服了其抑制平台现象，增强了其对肺癌的选择性抗肿瘤作用。代表性衍生物F9可以在NCI-H1975细胞的线粒体中积累，诱导细胞凋亡和细胞内活性氧的剂量依赖性增加并减少MMP。此外，在正常细胞BEAS-2B中没有观察到任何影响。体内研究表明， F9对斑马鱼的发育、肾脏和肝脏毒性均显着低于雷公藤甲素。这项研究为缓解雷公藤甲素的毒性问题提供了一个有前景的思路。
• Design and Synthesis of Novel C14-Hydroxyl Substituted Triptolide Derivatives as Potential Selective Antitumor Agents
  作者：Zheng Li、Zhao-Li Zhou、Ze-Hong Miao、Li-Ping Lin、Hui-Jin Feng、Lin-Jiang Tong、Jian Ding、Yuan-Chao Li

  DOI：10.1021/jm900342g

  日期：2009.8.27

  It has long been considered that the free beta hydroxyl group at C14 of triptolide(1) is essential to its potent anticancer activity. In this study, we synthesized novel derivatives of 1 with a hydroxyl group substituted by epoxy groups (4-8) ora five-membered ring (11-13). Compounds (4-8) showed significant in vitro anticancer activity although less potent than 1. Although with an alpha oxygen configuration at the C14 position, (14S)-14,21-epoxytriptolide (4) exhibited the highest potency among all these derivatives, clearly challenging the traditional viewpoint on the necessity of C14 beta-hydroxyl group of compound 1. Further studies revealed that while displaying broad spectrum ill vitro anticancer activity, compound 4 demonstrated prominent selective in vivo anticancer activity, particularly against human ovarian SK-OV-3 and prostate PC-3 cancers with obviously lower toxicity than 1. Noticeably, compound 4 was also highly effective against multidrug resistant cancer cells. Therefore, our study gives new insights into the structure-activity relationship of I and also produces a promising anticancer drug candidate with unique anticancer activities.