基于hymenialdisine骨架的多靶点抗阿尔茨海默病衍生物的设计、合成及生物活性研究

Alzheimer's disease is a progressive neurological disorder which is characterized by memory loss and cognitive decline. With the society aging the incidences of Alzheimer's disease is increasing. Due to the complexity and multiple etiologies of AD, single-target drugs can only be used to alleviate the symptoms of AD, which hardly match with the ideal requirements of clinical medication. This program is aiming to design and synthesize a serial of novel lead compounds which have the potential to be utilized as muti-target-directed drugs in AD treatment. Marine natural product hymenialdisine and its derivatives have been reported to inhibit neurofibrillary degeneration tangled tau protein; Metal chelators have been developed to inhibit the degradation of amyloid-β which form the plaque deposition. Based on these results, we propose to combine the skeleton of hymenialdisine with metal chelators, further hybridize these scaffolds with functional groups with anti-AChE activity to accomplish the structures of novel lead compounds. These small molecules will beevluated by optimized Ellman method, MTT colorimetric assay, Kinase-Glo luminescent kinase assay determine their in vitro inhibitory activity towards AChE, Aβ42, CDK5 and GSK-3β, respectively. The cytotoxicity of these compounds will be estimated with application of human SH-SY5Y cells. With the design, synthesis and biological evaluation of these lead compounds this project may provide beneficial information to understand the structure-activity relationship for developing novel multi-target-directed AD medications.

阿尔茨海默病是一种起病隐匿的进行性发展的神经系统退行性疾病，近年来随着社会的老龄化，发病率持续攀升。由于该疾病病因相对多样且复杂，现有单靶点药物普遍存在只能缓解不能根治的缺陷，无法满足临床用药需求。本项目从AD患者神经元纤维异常缠结及老年斑沉积两大紧密相关的病理特征出发，拟以能作用于神经元纤维异常缠结的tau抑制剂-天然产物hymenialdisine为基本骨架，首先与可抑制老年斑沉积核心成分Aβ聚集的金属螯合剂片段对接，然后骈合具抗乙酰胆碱酯酶活性的药效基团进行前药化处理，最终设计、合成一系列多靶点抗AD药物先导分子。应用Ellman法、MTT比色法、激酶发光检测法分别对所设计得到的化合物进行磷酸激酶、Aβ42、 CDK5激酶及GSK-3β激酶的体外抑制活性评估，并采用人体SH-SY5Y细胞对药物分子进行细胞毒性考察。本项目将为深入理解抗AD多靶点新型药物构效关系和新药设计提供有益思路。