6-chloracetyl triptolide ester | 1050619-26-5

• 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: 6-chloracetyl triptolide ester
• CAS: 1050619-26-5
• 化学式: C₂₂H₂₅ClO₇
• 分子量: 436.889
• InChiKey: YLFBHXCNVAWAEK-FSXSRNTLSA-N

物化性质

• 熔点：
  122-124 °C
• 沸点：
  608.8±55.0 °C(Predicted)
• 密度：
  1.49±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.89
• 重原子数：
  30.0
• 可旋转键数：
  3.0
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  90.19
• 氢给体数：
  0.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  6-chloracetyl triptolide ester 在 sodium iodide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 4.67h， 生成 C₂₂H₂₆O₈
  参考文献：
  名称：

  Discovery of a novel water-soluble, rapid-release triptolide prodrug with improved drug-like properties and high efficacy in human acute myeloid leukemia

  摘要：

  DOI：

  10.1016/j.ejmech.2022.114694
• 作为产物：
  描述：

  雷公藤甲素 、 氯乙酰氯 在 4-二甲氨基吡啶 作用下， 以 二氯甲烷 为溶剂， 反应 12.0h， 以88.8%的产率得到6-chloracetyl triptolide ester
  参考文献：
  名称：

  一类雷公藤甲素前药、其制备方法及其医药用途

  摘要：

  本发明公开了一类雷公藤甲素前药、其制备方法及其医药用途。属于药物化学领域；制备步骤：1、雷公藤甲素在DMAP的作用下与酰氯反应生成中间体II；2、中间体II在碘化钠和碳酸钾的作用下与羧酸化合物反应生成化合物III；3、化合物III与酸成盐得到目标化合物I。本发明具有更好的水溶性和药代动力学性质，相比Minnelide，具有更快的体内血液环境下的转化速度，更高效的合成方法，对恶性肿瘤、炎症性疾病、自身免疫性疾病等具有较好的治疗作用；另外；由于其水溶性好，不仅口服有效，还可以制成注射剂使用。

  公开号：

  CN114478684A

文献信息

• Design, synthesis, and biological evaluation of novel water-soluble triptolide derivatives: Antineoplastic activity against imatinib-resistant CML cells bearing T315I mutant Bcr-Abl
  作者：Fang Xu、Xianping Shi、Shichang Li、Jieshun Cui、Zhongzheng Lu、Yanli Jin、Yongcheng Lin、Jiyan Pang、Jingxuan Pan

  DOI：10.1016/j.bmc.2010.01.052

  日期：2010.3

  Imatinib (STI571) is the frontline targeted-therapeutic agent for patients with chronic myelogenous leukemia (CML). However, resistance to imatinib due to point mutations in Bcr-Abl kinase domain is an emerging problem. We recently reported that triptolide (compound 1) could effectively kill CML cells including those harboring T315I mutant Bcr-Abl. In the present study, we designed a series of C-14 triptolide derivatives with C-14-hydroxyl substituted by different amine esters (3-18): 3-6 and 13 (by aliphatic chain amine esters); 7-9, 11, 12 and 15-18 (by alicyclic amine esters with different size), and 10 and 14 (by aralkylamine esters). The compounds were examined for their antineoplastic activity against CML cells (including KBM5-T315I cells) in terms of proliferation inhibition, apoptosis and signal transduction. Nude mouse xenograft model was also used to evaluate the in vivo activity. Compounds 2-9, 11-14, 17 and 18 exhibited a potent inhibitory activity against KBM5 and KBM5-T315I cells. This series of derivatives down-regulated Bcr-Abl mRNA. Compounds 4, 5, 8 and 9 were further examined for their impact on signaling and apoptosis with immunoblotting. Compound 5 was chosen for evaluation in a nude mouse xenograft model. The stereo-hindrance of C-14 group appeared to be responsible for the antitumor effect. The computational small molecule-protein docking analysis illustrated the possible interaction between compound 9 and RNA polymerase II. Our results suggest that this series of derivatives may be promising agents to overcome imatinib-resistance caused by the Bcr-Abl-T315I mutation. (C) 2010 Elsevier Ltd. All rights reserved.