7',8'-Dihydro-2'-methoxy-8'-methylspiro[1,3-dioxolane-2,6'(5'H)quinoline] | 182173-77-9

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 7',8'-Dihydro-2'-methoxy-8'-methylspiro[1,3-dioxolane-2,6'(5'H)quinoline]
• 英文别名: (+/-)-7',8'-dihydro-2'-methoxy-8'-methylspiro(1,3-dioxolane-2,6'(5'H)quinoline)；2'-methoxy-8'-methylspiro[1,3-dioxolane-2,6'-7,8-dihydro-5H-quinoline]
• CAS: 182173-77-9
• 化学式: C₁₃H₁₇NO₃
• 分子量: 235.283
• InChiKey: NPBOWQGGWTWMJB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.6
• 重原子数：
  17
• 可旋转键数：
  1
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  40.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  7',8'-Dihydro-2'-methoxy-8'-methylspiro[1,3-dioxolane-2,6'(5'H)quinoline] 在 盐酸 作用下， 以 丙酮 为溶剂， 反应 3.0h， 以96%的产率得到2-Methoxy-8-methyl-7,8-dihydro-5H-quinolin-6-one
  参考文献：
  名称：

  Identification of a More Potent Analogue of the Naturally Occurring Alkaloid Huperzine A. Predictive Molecular Modeling of Its Interaction with AChE

  摘要：

  Huperzine A (HA), a potent reversible inhibitor of acetylcholinesterase (AChE), is an important psychotherapeutic agent for improving cognitive function in Alzheimer's patients through the enhancement of central cholinergic tone. This molecule takes on added value in that it has recently been shown to exhibit neuroprotective properties (glutamate toxicity blocking activity) in vitro. Based upon our cumulative SAR information and to some extent the predicted binding site of HA within Torpedo AChE, we chose to investigate the synthesis and biology of certain C-10 substituted analogues. The important finding was made that introduction of an axial methyl group into the C-10 position of huperzine A increased the potency for AChE inhibition 8-fold; the corresponding equatorial isomer was about 1.5-fold less active than huperzine A. The introduction of substituents larger than methyl resulted in a drop in activity. For example, the ethyl analogue was found to be about 100-fold less active than huperzine A, indicating that while it is still capable of binding to Torpedo AChE, some steric interaction with the ''walls'' of the active site gorge must result. Through the use of molecular modeling methods involving the docking of these analogues to the reported X-ray crystal structure of Torpedo AChE, it is clearly evident that the C-10 axial methyl group points into a hydrophobic region of the enzyme, while the equatorial methyl group is directed to a less favorable hydrophilic region. Substituents larger than methyl were found to result in a conformational energy penalty. The ready explanation of this structure-activity relationship data provides further evidence in support of our modeling studies aimed at establishing huperzine A's binding site in AChE. This knowledge should facilitate the identification of other structural analogues of huperzine A likely to exhibit an improved therapeutic profile.

  DOI：

  10.1021/ja9622822
• 作为产物：
  描述：

  7-甲基-1,4-二氧杂-螺[4.5]癸烷-8-酮 在 氨 、 silver carbonate 作用下， 以 甲醇 、 氯仿 为溶剂， 反应 14.0h， 生成 7',8'-Dihydro-2'-methoxy-8'-methylspiro[1,3-dioxolane-2,6'(5'H)quinoline]
  参考文献：
  名称：

  Identification of a More Potent Analogue of the Naturally Occurring Alkaloid Huperzine A. Predictive Molecular Modeling of Its Interaction with AChE

  摘要：

  Huperzine A (HA), a potent reversible inhibitor of acetylcholinesterase (AChE), is an important psychotherapeutic agent for improving cognitive function in Alzheimer's patients through the enhancement of central cholinergic tone. This molecule takes on added value in that it has recently been shown to exhibit neuroprotective properties (glutamate toxicity blocking activity) in vitro. Based upon our cumulative SAR information and to some extent the predicted binding site of HA within Torpedo AChE, we chose to investigate the synthesis and biology of certain C-10 substituted analogues. The important finding was made that introduction of an axial methyl group into the C-10 position of huperzine A increased the potency for AChE inhibition 8-fold; the corresponding equatorial isomer was about 1.5-fold less active than huperzine A. The introduction of substituents larger than methyl resulted in a drop in activity. For example, the ethyl analogue was found to be about 100-fold less active than huperzine A, indicating that while it is still capable of binding to Torpedo AChE, some steric interaction with the ''walls'' of the active site gorge must result. Through the use of molecular modeling methods involving the docking of these analogues to the reported X-ray crystal structure of Torpedo AChE, it is clearly evident that the C-10 axial methyl group points into a hydrophobic region of the enzyme, while the equatorial methyl group is directed to a less favorable hydrophilic region. Substituents larger than methyl were found to result in a conformational energy penalty. The ready explanation of this structure-activity relationship data provides further evidence in support of our modeling studies aimed at establishing huperzine A's binding site in AChE. This knowledge should facilitate the identification of other structural analogues of huperzine A likely to exhibit an improved therapeutic profile.

  DOI：

  10.1021/ja9622822

文献信息

• US5547960A
  申请人：——

  公开号：US5547960A

  公开（公告）日：1996-08-20
• Identification of a More Potent Analogue of the Naturally Occurring Alkaloid Huperzine A. Predictive Molecular Modeling of Its Interaction with AChE
  作者：Alan P. Kozikowski、Giuseppe Campiani、Li-Qiang Sun、Shaomeng Wang、Ashima Saxena、Bhupendra P. Doctor

  DOI：10.1021/ja9622822

  日期：1996.1.1

  Huperzine A (HA), a potent reversible inhibitor of acetylcholinesterase (AChE), is an important psychotherapeutic agent for improving cognitive function in Alzheimer's patients through the enhancement of central cholinergic tone. This molecule takes on added value in that it has recently been shown to exhibit neuroprotective properties (glutamate toxicity blocking activity) in vitro. Based upon our cumulative SAR information and to some extent the predicted binding site of HA within Torpedo AChE, we chose to investigate the synthesis and biology of certain C-10 substituted analogues. The important finding was made that introduction of an axial methyl group into the C-10 position of huperzine A increased the potency for AChE inhibition 8-fold; the corresponding equatorial isomer was about 1.5-fold less active than huperzine A. The introduction of substituents larger than methyl resulted in a drop in activity. For example, the ethyl analogue was found to be about 100-fold less active than huperzine A, indicating that while it is still capable of binding to Torpedo AChE, some steric interaction with the ''walls'' of the active site gorge must result. Through the use of molecular modeling methods involving the docking of these analogues to the reported X-ray crystal structure of Torpedo AChE, it is clearly evident that the C-10 axial methyl group points into a hydrophobic region of the enzyme, while the equatorial methyl group is directed to a less favorable hydrophilic region. Substituents larger than methyl were found to result in a conformational energy penalty. The ready explanation of this structure-activity relationship data provides further evidence in support of our modeling studies aimed at establishing huperzine A's binding site in AChE. This knowledge should facilitate the identification of other structural analogues of huperzine A likely to exhibit an improved therapeutic profile.