tetraethyl (Z)-(2-(1-(3,7-dimethylocta-2,6-dien-1-yl)-1H-1,2,3-triazol-4-yl)ethane-1,1-diyl)bis(phosphonate) | 1418665-51-6

• 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: tetraethyl (Z)-(2-(1-(3,7-dimethylocta-2,6-dien-1-yl)-1H-1,2,3-triazol-4-yl)ethane-1,1-diyl)bis(phosphonate)
• CAS: 1418665-51-6
• 化学式: C₂₂H₄₁N₃O₆P₂
• 分子量: 505.532
• InChiKey: ADWRRFZTCQEOBF-HKWRFOASSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.37
• 重原子数：
  33.0
• 可旋转键数：
  17.0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.73
• 拓扑面积：
  101.77
• 氢给体数：
  0.0
• 氢受体数：
  9.0

反应信息

• 作为反应物：
  描述：

  tetraethyl (Z)-(2-(1-(3,7-dimethylocta-2,6-dien-1-yl)-1H-1,2,3-triazol-4-yl)ethane-1,1-diyl)bis(phosphonate) 在 三甲基溴硅烷 作用下， 以 二氯甲烷 为溶剂， 生成 [2-[1-[(2Z)-3,7-dimethylocta-2,6-dienyl]triazol-4-yl]-1-phosphonoethyl]phosphonic acid
  参考文献：
  名称：

  Geranyl and neryl triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase

  摘要：

  When inhibitors of enzymes that utilize isoprenoid pyrophosphates are based on the natural substrates, a significant challenge can be to achieve selective inhibition of a specific enzyme. One element in the design process is the stereochemistry of the isoprenoid olefins. We recently reported preparation of a series of isoprenoid triazoles as potential inhibitors of geranylgeranyl transferase II but these compounds were obtained as a mixture of olefin isomers. We now have accomplished the stereoselective synthesis of these triazoles through the use of epoxy azides for the cycloaddition reaction followed by regeneration of the desired olefin. Both geranyl and neryl derivatives have been prepared as single olefin isomers through parallel reaction sequences. The products were assayed against multiple enzymes as well as in cell culture studies and surprisingly a Z-olefin isomer was found to be a potent and selective inhibitor of geranylgeranyl diphosphate synthase. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.03.014
• 作为产物：
  描述：

  (2R,3S)-2,3-epoxynerol 在 sodium azide 、 copper(II) sulfate 、 甲基磺酰氯 、 sodium ascorbate 、 三氟乙酸 、 sodium iodide 、 lithium bromide 作用下， 以 四氢呋喃 、 水 、 乙腈 、 叔丁醇 为溶剂， 反应 0.08h， 生成 tetraethyl (Z)-(2-(1-(3,7-dimethylocta-2,6-dien-1-yl)-1H-1,2,3-triazol-4-yl)ethane-1,1-diyl)bis(phosphonate)
  参考文献：
  名称：

  Geranyl and neryl triazole bisphosphonates as inhibitors of geranylgeranyl diphosphate synthase

  摘要：

  When inhibitors of enzymes that utilize isoprenoid pyrophosphates are based on the natural substrates, a significant challenge can be to achieve selective inhibition of a specific enzyme. One element in the design process is the stereochemistry of the isoprenoid olefins. We recently reported preparation of a series of isoprenoid triazoles as potential inhibitors of geranylgeranyl transferase II but these compounds were obtained as a mixture of olefin isomers. We now have accomplished the stereoselective synthesis of these triazoles through the use of epoxy azides for the cycloaddition reaction followed by regeneration of the desired olefin. Both geranyl and neryl derivatives have been prepared as single olefin isomers through parallel reaction sequences. The products were assayed against multiple enzymes as well as in cell culture studies and surprisingly a Z-olefin isomer was found to be a potent and selective inhibitor of geranylgeranyl diphosphate synthase. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.03.014

文献信息

• α-Methylation enhances the potency of isoprenoid triazole bisphosphonates as geranylgeranyl diphosphate synthase inhibitors
  作者：Robert A. Matthiesen、Michelle L. Varney、Pauline C. Xu、Alex S. Rier、David F. Wiemer、Sarah A. Holstein

  DOI：10.1016/j.bmc.2017.10.023

  日期：2018.1

  malignancies, especially those characterized by excessive protein secretion such as multiple myeloma. Our work has demonstrated that some isoprenoid triazole bisphosphonates are potent and selective inhibitors of GGDPS. Here we present the synthesis and biological evaluation of a new series of isoprenoid triazoles modified by incorporation of a methyl group at the α-carbon. These studies reveal that incorporation

  通过抑制香叶基香叶基二磷酸合酶（GGDPS）来破坏蛋白质香叶基香叶基化代表了一种针对多种恶性肿瘤的新治疗策略，特别是那些以蛋白质过度分泌为特征的恶性肿瘤，例如多发性骨髓瘤。我们的工作表明，一些类异戊二烯三唑二膦酸盐是 GGDPS 的有效且选择性抑制剂。在这里，我们介绍了通过在 α-碳上掺入甲基进行修饰的一系列新的类异戊二烯三唑的合成和生物学评价。这些研究表明，α-甲基取代基的引入增强了这些化合物作为 GGDPS 抑制剂的效力，并且在高香叶基/高香基系列的情况下，消除了烯烃立体化学对抑制活性的影响。甲基的掺入允许制备 POM 前药，与相应的盐相比，其细胞活性增加了 10 倍。这些研究为未来研究这些新型 α-甲基三唑二膦酸盐的抗骨髓瘤活性的临床前研究奠定了基础。