Synthesis and characterization of 1H-phenanthro[9,10-d]imidazole derivatives as multifunctional agents for treatment of Alzheimer's disease.
Synthesis and characterization of 1H-phenanthro[9,10-d]imidazole derivatives as multifunctional agents for treatment of Alzheimer's disease.
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1H-菲并[9,10-d]咪唑衍生物的合成和表征作为治疗阿尔茨海默病的多功能药物。
DOI：
10.1016/j.bbagen.2014.05.005
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Ding Li
中科院分区：
文献类型：
--
作者：
Jinggong Liu;J. Qiu;Mingxue Wang;Ling Wang;L. Su;Jinbo Gao;Qiong Gu;Jun Xu;Shi;L. Gu;Zhishu Huang;Ding Li
研究背景阿尔茨海默病（Alzheimer's disease，AD）是一种以痴呆、认知功能障碍和记忆丧失为特征的进行性神经退行性疾病。AD的发生与多种因素有关，如β-淀粉样蛋白（Aβ）、乙酰胆碱、金属离子失调、tau蛋白过度磷酸化和氧化应激等。1H-菲并[9，10-d]咪唑衍生物的有机合成，自身介导和金属诱导的Aβ1- 42聚集的抑制，乙酰胆碱酯酶和丁酰胆碱酯酶的抑制研究，结果合成并表征了一种新型的1H-菲并[9，10-d]咪唑类多功能抗AD药物。结果表明，大部分衍生物具有较强的Aβ聚集抑制活性。化合物9 g在10 μM浓度下对Aβ1- 42聚集有74%的抑制作用，其对自身诱导的Aβ1- 42聚集的IC 50值为6.5 μM。硫代黄素T法、透射电镜、凝胶电泳和Western blot结果表明，该化合物对金属离子（Cu ~（2+）和Fe ~（2+））和乙酰胆碱酯酶诱导的Aβ1- 42聚集有良好的抑制作用。化合物9 g对乙酰胆碱酯酶和丁酰胆碱酯酶的IC_（50）分别为0.86 μM和0.51 μM。此外，化合物9 g具有良好的抗氧化作用，ORAC值为2.29。结论化合物9 g是一种有效的多靶点治疗阿尔茨海默病的药物，具有广阔的应用前景。
BackgroundAlzheimer's disease (AD) is a progressive neurodegenerative brain disorder that is characterized by dementia, cognitive impairment, and memory loss. Diverse factors are related to the development of AD, such as increased level ofβ-amyloid (Aβ), acetylcholine, metal ion deregulation, hyperphosphorylated tau protein, and oxidative stress.MethodsThe following methods were used: organic syntheses of 1H-phenanthro[9,10-d]imidazole derivatives, inhibition of self-mediated and metal-induced Aβ1–42aggregation, inhibition studies for acetylcholinesterase and butyrylcholinesterase, anti-oxidation activity studies, CD, MTT assay, transmission electron microscopy, dot plot assay, gel electrophoresis, Western blot, and molecular docking studies.ResultsWe synthesized and characterized a new type of 1H-phenanthro[9,10-d]imidazole derivatives as multifunctional agents for AD treatment. Our results showed that most of these derivatives exhibited strong Aβaggregation inhibitory activity. Compound9ghad 74% Aβ1–42aggregation inhibitory effect at 10 μM concentration with its IC50value of 6.5 μM for self-induced Aβ1–42aggregation. This compound also showed good inhibition of metal-mediated (Cu2 +and Fe2 +) and acetylcholinesterase-induced Aβ1–42aggregation, as indicated by using thioflavin T assay, transmission electron microscopy, gel electrophoresis, and Western blot. Besides, compound9gexhibited cholinesterase inhibitory activity, with its IC50values of 0.86 μM and 0.51 μM for acetylcholinesterase and butyrylcholinesterase, respectively. In addition, compound9gshowed good anti-oxidation effect with oxygen radical absorbance capacity (ORAC) value of 2.29.ConclusionsCompound9gwas found to be a potent multi-target-directed agent for Alzheimer's disease.General significanceCompound9gcould become a lead compound for further development as a multi-target-directed agent for AD treatment.
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影响因子：
14.8
作者：
Bieschke, Jan;Herbst, Martin;Wanker, Erich E.
通讯作者：
Wanker, Erich E.
影响因子：
3.2
作者：
J. Moses;Dougal J. Ritson;Fengzhi Zhang;C. Lombardo;S. Haider;N. Oldham;S. Neidle
通讯作者：
J. Moses;Dougal J. Ritson;Fengzhi Zhang;C. Lombardo;S. Haider;N. Oldham;S. Neidle
影响因子：
15
作者：
Harel, Michal;Sonoda, Leilani K.;Rosenberry, Terrone L.
通讯作者：
Rosenberry, Terrone L.
DOI：
10.1073/pnas.91.25.12243
发表时间：
1994-12-06
影响因子：
11.1
作者：
LORENZO, A;YANKNER, BA
通讯作者：
YANKNER, BA