9-N-isobutyl-8-isobutyloxy-manzamine A

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 哈马拉生物碱
• 英文名称: 9-N-isobutyl-8-isobutyloxy-manzamine A
• 英文别名: (1R,2R,4R,5Z,12R,13S,16Z)-25-[8-(2-methylpropoxy)-9-(2-methylpropyl)pyrido[3,4-b]indol-1-yl]-11,22-diazapentacyclo[11.11.2.12,22.02,12.04,11]heptacosa-5,16,25-trien-13-ol
• 化学式: C₄₄H₆₀N₄O₂
• 分子量: 676.986
• InChiKey: ARTZKRLNCMHAJE-PVCRYNGISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  8.2
• 重原子数：
  50
• 可旋转键数：
  6
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.61
• 拓扑面积：
  53.8
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  碘代异丁烷 、 8-Hydroxymanzamine A 在 potassium carbonate 作用下， 以 丙酮 为溶剂， 以75%的产率得到9-N-isobutyl-8-isobutyloxy-manzamine A
  参考文献：
  名称：

  Glycogen Synthase Kinase-3 (GSK-3) Inhibitory Activity and Structure–Activity Relationship (SAR) Studies of the Manzamine Alkaloids. Potential for Alzheimer’s Disease

  摘要：

  Manzamine A and related derivatives isolated from a common Indonesian sponge, Acanthostrongylophora, have been identified as a new class of GSK-3 beta inhibitors. The semisynthesis of new analogues and the first structure-activity relationship studies with GSK-3 beta are also reported. Moreover, manzamine A proved to be effective in decreasing tau hyperphosphorylation in human neuroblastoma cell lines, a demonstration of its ability to enter cells and interfere with tau pathology. Inhibition studies of manzamine A against a selected panel of five different kinases related to GSK-3 beta, specifically CDK-1, PKA, CDK-5, MAPK, and GSK-3 alpha, show the specific inhibition of manzamine A on GSK-3 beta and CDK-5, the two kinases involved in tau pathological hyperphosphorylation. These results suggest that manzamine A constitutes a promising scaffold from which more potent and selective GSK-3 inhibitors could be designed as potential therapeutic agents for Alzheimer's disease.

  DOI：

  10.1021/np060092r

文献信息

• Glycogen Synthase Kinase-3 (GSK-3) Inhibitory Activity and Structure–Activity Relationship (SAR) Studies of the Manzamine Alkaloids. Potential for Alzheimer’s Disease
  作者：Mark Hamann、Diana Alonso、Ester Martín-Aparicio、Ana Fuertes、M. José Pérez-Puerto、Ana Castro、Susana Morales、María Luisa Navarro、María del Monte-Millán、Miguel Medina、Hari Pennaka、Akula Balaiah、Jiangnan Peng、Jennifer Cook、Subagus Wahyuono、Ana Martínez

  DOI：10.1021/np060092r

  日期：2007.9.1

  Manzamine A and related derivatives isolated from a common Indonesian sponge, Acanthostrongylophora, have been identified as a new class of GSK-3 beta inhibitors. The semisynthesis of new analogues and the first structure-activity relationship studies with GSK-3 beta are also reported. Moreover, manzamine A proved to be effective in decreasing tau hyperphosphorylation in human neuroblastoma cell lines, a demonstration of its ability to enter cells and interfere with tau pathology. Inhibition studies of manzamine A against a selected panel of five different kinases related to GSK-3 beta, specifically CDK-1, PKA, CDK-5, MAPK, and GSK-3 alpha, show the specific inhibition of manzamine A on GSK-3 beta and CDK-5, the two kinases involved in tau pathological hyperphosphorylation. These results suggest that manzamine A constitutes a promising scaffold from which more potent and selective GSK-3 inhibitors could be designed as potential therapeutic agents for Alzheimer's disease.