methyl 2-[(2R,4aR,6S,7R,8aS)-7-methyl-2-phenyl-7-trimethylsilyloxy-4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-6-yl]acetate | 1190598-94-7

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: methyl 2-[(2R,4aR,6S,7R,8aS)-7-methyl-2-phenyl-7-trimethylsilyloxy-4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-6-yl]acetate
• CAS: 1190598-94-7
• 化学式: C₂₀H₃₀O₆Si
• 分子量: 394.54
• InChiKey: NZEDKADRYQEUDB-YQXATGRUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.43
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  63.2
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl 2-[(2R,4aR,6S,7R,8aS)-7-methyl-2-phenyl-7-trimethylsilyloxy-4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-6-yl]acetate 在 四丁基氟化铵 、 sodium hexamethyldisilazane 、 二异丁基氢化铝 作用下， 以 四氢呋喃 、 正己烷 、 二氯甲烷 为溶剂， 反应 3.58h， 生成
  参考文献：
  名称：

  Design and Synthesis of Skeletal Analogues of Gambierol: Attenuation of Amyloid-β and Tau Pathology with Voltage-Gated Potassium Channel and N-Methyl-d-aspartate Receptor Implications

  摘要：

  Gambierol is a potent neurotoxin that belongs to the family of marine polycyclic ether natural products and primarily targets voltage-gated potassium channels (K-v channels) in excitable membranes. Previous work in the chemistry of marine polycyclic ethers has suggested the critical importance of the full length of polycyclic ether skeleton for potent biological activity. Although we have previously investigated structure-activity relationships (SARs) of the peripheral functionalities of gambierol, it remained unclear whether the whole polycyclic ether skeleton is needed for its cellular activity. In this work, we designed and synthesized two truncated skeletal analogues of gambierol comprising the EFGH- and BCDEFGH-rings of the parent compound, both of which surprisingly showed similar potency to gambierol on voltage gated potassium channels (K-v) inhibition. Moreover, we examined the effect of these compounds in an in vitro model of Alzheimer's disease (AD) obtained from triple transgenic (3xTg-AD) mice, which expresses amyloid beta (A beta) accumulation and tau hyperphosphorylation. In vitro preincubation of the cells with the compounds resulted in significant inhibition of K+ currents, a reduction in the extra- and intracellular levels of A beta, and a decrease in the levels of hyperphosphorylated tau. In addition, pretreatment with these compounds reduced the steady-state level of the N-methyl-D-aspartate (NMDA) receptor subunit 2A without affecting the 2B subunit. The involvement of glutamate receptors was further suggested by the blockage of the effect of gambierol on tau hyperphosphorylation by glutamate receptor antagonists. The present study constitutes the first discovery of skeletally simplified, designed polycyclic ethers with potent cellular activity and demonstrates the utility of gambierol and its synthetic analogues as chemical probes for understanding the function of K-v channels as well as the molecular mechanism of A beta metabolism modulated by NMDA receptors.

  DOI：

  10.1021/ja300565t
• 作为产物：
  描述：

  三氟甲磺酸三甲基硅酯 、 在 2,6-二甲基吡啶 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 以100%的产率得到methyl 2-[(2R,4aR,6S,7R,8aS)-7-methyl-2-phenyl-7-trimethylsilyloxy-4a,6,8,8a-tetrahydro-4H-pyrano[3,2-d][1,3]dioxin-6-yl]acetate
  参考文献：
  名称：

  甘菊酸的全合成研究：DEFG-Ring模型化合物的立体控制合成

  摘要：

  基于铃木-Miyaura偶联，已经完成了冈比亚酸DEFG环模型化合物（高效抗真菌海洋多环醚天然产物）的立体控制收敛性合成。对模型化合物的构象分析表明，与雪茄毒素相反，该九元F环仅作为一个稳定的构象体存在。

  DOI：

  10.1021/jo1008146

文献信息

• Design and Synthesis of Skeletal Analogues of Gambierol: Attenuation of Amyloid-β and Tau Pathology with Voltage-Gated Potassium Channel and <i>N</i>-Methyl-<scp>d</scp>-aspartate Receptor Implications
  作者：Eva Alonso、Haruhiko Fuwa、Carmen Vale、Yuto Suga、Tomomi Goto、Yu Konno、Makoto Sasaki、Frank M. LaFerla、Mercedes R. Vieytes、Lydia Giménez-Llort、Luis M. Botana

  DOI：10.1021/ja300565t

  日期：2012.5.2

  Gambierol is a potent neurotoxin that belongs to the family of marine polycyclic ether natural products and primarily targets voltage-gated potassium channels (K-v channels) in excitable membranes. Previous work in the chemistry of marine polycyclic ethers has suggested the critical importance of the full length of polycyclic ether skeleton for potent biological activity. Although we have previously investigated structure-activity relationships (SARs) of the peripheral functionalities of gambierol, it remained unclear whether the whole polycyclic ether skeleton is needed for its cellular activity. In this work, we designed and synthesized two truncated skeletal analogues of gambierol comprising the EFGH- and BCDEFGH-rings of the parent compound, both of which surprisingly showed similar potency to gambierol on voltage gated potassium channels (K-v) inhibition. Moreover, we examined the effect of these compounds in an in vitro model of Alzheimer's disease (AD) obtained from triple transgenic (3xTg-AD) mice, which expresses amyloid beta (A beta) accumulation and tau hyperphosphorylation. In vitro preincubation of the cells with the compounds resulted in significant inhibition of K+ currents, a reduction in the extra- and intracellular levels of A beta, and a decrease in the levels of hyperphosphorylated tau. In addition, pretreatment with these compounds reduced the steady-state level of the N-methyl-D-aspartate (NMDA) receptor subunit 2A without affecting the 2B subunit. The involvement of glutamate receptors was further suggested by the blockage of the effect of gambierol on tau hyperphosphorylation by glutamate receptor antagonists. The present study constitutes the first discovery of skeletally simplified, designed polycyclic ethers with potent cellular activity and demonstrates the utility of gambierol and its synthetic analogues as chemical probes for understanding the function of K-v channels as well as the molecular mechanism of A beta metabolism modulated by NMDA receptors.
• Studies toward the Total Synthesis of Gambieric Acids: Stereocontrolled Synthesis of a DEFG-Ring Model Compound
  作者：Haruhiko Fuwa、Sayaka Noji、Makoto Sasaki

  DOI：10.1021/jo1008146

  日期：2010.8.6

  A stereocontrolled convergent synthesis of a DEFG-ring model compound of gambieric acids, highly potent antifungal marine polycyclic ether natural products, has been achieved based on Suzuki—Miyaura coupling. Conformational analysis of the model compound revealed that the nine-membered F-ring exists exclusively as a single stable conformer, as opposed to that of ciguatoxins.

  基于铃木-Miyaura偶联，已经完成了冈比亚酸DEFG环模型化合物（高效抗真菌海洋多环醚天然产物）的立体控制收敛性合成。对模型化合物的构象分析表明，与雪茄毒素相反，该九元F环仅作为一个稳定的构象体存在。