Chen Yan, Bian Yuemin, Wang Jian-Wei, Gong Ting-Ting, Ying You-Min, Ma Lie-Feng, Shan Wei-Guang, Xie Xiang-Qun, Zhan Zha-Jun
College of Pharmacology Sciences Zhejiang University of Technology, Hangzhou 310014, P. R. China.
Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy; NIH National Center of Excellence for Computational Drug Abuse Research; Drug Discovery Institute; Departments of Computational Biology and Structural Biology, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, United States.
ACS Omega. 2020 Apr 23;5(17):9846-9863. doi: 10.1021/acsomega.0c00057. eCollection 2020 May 5.
α-Mangostin (α-M) is a natural xanthone from the pericarp of fruit and possesses versatile biological activities. α-M has a therapeutic potential to treat Alzheimer's disease (AD) because of its anti-inflammatory, antioxidative, and neuroprotective activities. However, the use of α-M for AD treatment is limited due to its cytotoxic activities and relatively low potency. Modifications of its chemical structure were needed to reduce its cytotoxicity and improve its therapeutic potential against AD. For this purpose, 16 α-M carbamate derivatives were synthesized. An animal model of AD was established, and the effects of on the spatial learning ability and memory ability were evaluated using behavioral tests. The effect on neuropathology was tested by histopathological evaluation, Nissl staining, and silver staining. Computational systems pharmacology analysis using the chemogenomics knowledgebase was applied for network studies. Compound-target, target-pathway, and target-disease networks were constructed, integrating both analysis and reported experimental data. The results show that can demonstrate its therapeutic effects in a one-molecule, multiple-targets manner to remarkably ameliorate neurological changes and reverse behavioral deficits in AD model rats. The improved cognitive function and alleviated neuronal injury can be observed. The ability of to scavenge β-amyloid in the hippocampus was validated in AD model rats.
α-山竹黄酮（α-M）是一种从水果果皮中提取的天然氧杂蒽酮，具有多种生物活性。由于其抗炎、抗氧化和神经保护活性，α-M具有治疗阿尔茨海默病（AD）的潜力。然而，由于其细胞毒性活性和相对较低的效力，α-M在AD治疗中的应用受到限制。需要对其化学结构进行修饰，以降低其细胞毒性并提高其对AD的治疗潜力。为此，合成了16种α-M氨基甲酸酯衍生物。建立了AD动物模型，并通过行为测试评估了其对空间学习能力和记忆能力的影响。通过组织病理学评估、尼氏染色和银染色测试其对神经病理学的影响。使用化学基因组知识库进行计算系统药理学分析，用于网络研究。构建了化合物-靶点、靶点-通路和靶点-疾病网络，整合了分析和已报道的实验数据。结果表明，其可以以单分子、多靶点的方式发挥治疗作用，显著改善AD模型大鼠的神经变化并逆转行为缺陷。可以观察到认知功能的改善和神经元损伤的减轻。在AD模型大鼠中验证了其清除海马中β-淀粉样蛋白的能力。
