(2S,3S,4aR,8aS)-2-(iodomethyl)-3-((4-methoxybenzyl)oxy)-4a-methyloctahydropyrano[3,2-b]pyran | 1373516-87-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: (2S,3S,4aR,8aS)-2-(iodomethyl)-3-((4-methoxybenzyl)oxy)-4a-methyloctahydropyrano[3,2-b]pyran
• CAS: 1373516-87-0
• 化学式: C₁₈H₂₅IO₄
• 分子量: 432.299
• InChiKey: IAAKEVFCSCWVSK-XWTMOSNGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.74
• 重原子数：
  23.0
• 可旋转键数：
  5.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  36.92
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  (2S,3S,4aR,8aS)-2-(iodomethyl)-3-((4-methoxybenzyl)oxy)-4a-methyloctahydropyrano[3,2-b]pyran 在 咪唑 、 三乙基硅烷 、 4-二甲氨基吡啶 、 N-碘代丁二酰亚胺 、 四丙基高钌酸铵 、 dimethyl sulfide borane 、 potassium tert-butylate 、 sodium methylate 、 silver trifluoromethanesulfonate 、 zinc trifluoromethanesulfonate 、 caesium carbonate 、 N-甲基吗啉氧化物 、 三乙胺 、 2,3-二氯-5,6-二氰基-1,4-苯醌 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 33.67h， 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：

  在 咪唑 、 RuCl2(1,3-dimesityl-imidazolidin-2-yl)(PCy3)(=CHPh) 、 bis(1,5-cyclooctadiene)diiridium(I) dichloride 、 palladium on activated charcoal 、 氢气 、 碘 、 4-甲基苯磺酸吡啶 、 二异丁基氢化铝 、 sodium carbonate 、 三苯基膦 作用下， 以 四氢呋喃 、 乙醇 、 正己烷 、 二氯甲烷 、 甲苯 、 苯 为溶剂， 反应 105.67h， 生成 (2S,3S,4aR,8aS)-2-(iodomethyl)-3-((4-methoxybenzyl)oxy)-4a-methyloctahydropyrano[3,2-b]pyran
  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