阿尔茨海默氏病（AD）是最常见的一种老年痴呆症（dementia）。2015世界阿尔茨海默报告指出，现全球有4600万dementia患者，到2050年患者数将达1.3亿。国际上针对BACE1/GSK-3β等特异性酶抑制剂研发抗AD药物是研究的重点。多异戊烯基间苯三酚衍生物（PPAPs）是金丝桃属植物的特征成分，近年是天然药物化学的热点研究领域。申请人前期从大别山产该属植物发现了系列新型、生物活性的PPAPs。最近在神农架产该属植物中有了新的发现，初步的药理活性筛选显示部分PPAPs衍生物对Aβ42诱导HEK293细胞和OA 诱导 HEK293-tau 细胞损伤具有较好的保护作用。本项目拟系统开展两种金丝桃属植物，并基于BACE1、GSK-3β和PP2A等信号通路评价其次生代谢产物的抗AD作用及机制，以期发现有应用前景的抗AD药物先导物，为该属药用植物资源的持续开发利用提供科学依据。

Alzheimer's disease (AD) is one of the most common disease found in people live with dementia. Most recently, the World Alzheimer Report 2015 demonstrated that at present there are over 46 million people live with dementia worldwide, and this number is estimated to increase to 131.5 million by 2050. Currently, the research and development of new specific enzyme inhibitors against BACE1, GSK-3β and other related protein kinases are hot subject in the discovering effective anti-AD therapeutic agents throughout of the world. Polycyclic polyprenylated acylphloroglucinols (PPAPs) are naturally occurring metabolites that characterized as the main secondary metabolites produced by the plants of the genus Hypericum, which are one of the hot research area in the field of natural products chemistry. During our previous work, we had isolated and identified many bioactive PPAPs derivatives from several plants of the genus Hypericum that collected from Dabie mountains, and our current work made new breakthroughs in the investigation of chemical constituents of the medicinal plants collected from Shennongjia forestry district. In our preliminary biological evaluation of the anti-AD bioactivities of the isolated compounds from these plants, the in vitro screening the protective effect of PPAPs on the HEK293 and HEK293-tau cells damage caused by Aβ42 and OA, respectively . Based on this, the present work aims to systematically investigate the secondary metabolites of the selected species of the genus Hypericum with important medicinal use. In this project, the phytochemical isolation, purification, and structure elucidation of the natural products of the above-mentioned species from the genus Hypericum will be performed. Meanwhile, the in vitro anti-AD activities of the isolated compounds and their potential mechanisms of action will also be conducted through BACE1, GSK-3β, PP2A and related signaling pathways. The results of this project are expected to discover promising anti-AD agents from these medical plants, which in turn will not only provide reference value for the discovery of bioactive natural products as lead compounds with therapeutic application potential against Alzheimer's disease, but also offer scientific basis for the rational and sustainable utilization of these medicinal important plants.

近年来，金丝桃属（Hypericum）植物因含有的次生代谢产物种类众多、骨架类型多变、活性多样，尤其受到天然药物化学家的青睐。本项目在前期工作基础上，对华中神农架地区产金丝桃属植物贯叶金丝桃（H. perforatum）和长柱金丝桃(H. longistylum)乙醇提取物进行了化学成分及其抗AD活性研究，取得如下成果：1）通过植物化学研究，从以上两种金丝桃属植物中分离鉴定天然产物51个，包括19个新化合物，绝大部分为多环多异戊烯基间苯三酚类衍生物(PPAPs)；2）综合运用包括NMR,金属Rh盐诱导ECD，以及单晶X-ray衍射，Mosher法和量子化学计算等方法确定了这些新化合物的结构和绝对构型；3）抗AD生物活性筛选发现，5个PPAPs化合物具显著的AChE酶抑制活性；4）首次发现类金刚烷等PPAPs衍生物（如GY-7和GY-15）不仅可调节PP2A活性降低Tau蛋白磷酸化水平，还可调节BACE1活性减少APPβ和毒性Aβ的产生从而发挥双重抗AD作用。本项目相关研究到目前共发表标注的SCI 论文3 篇，其中在天然产物和有机化学研究领域著名学术期刊J. Org. Chem.（IF 4.849）发表研究论文一篇，在天然产物领域国际公认学术期刊J. Nat. Prod. 上发表论文两篇。申请国家发明专利一项。2个多环天然产物被Nat. Prod. Rep.杂志评为国际热点化合物（Hot off the Press）。本项目的深入展开，有望从金丝桃属植物次生代谢产物中发现新型具独特多靶点的抗阿尔茨海默症先导化合物，为金丝桃属药用植物物种资源的综合开发利用提供科学依据。