海洋天然产物Hyrtioseragamine B的合成、结构修饰及其多靶向抗阿尔茨海默症构效关系研究

Hyrtioseragamine B, an alkaloid isolated form marine sponge Hyrtios sp., is the first natural product possessing a furo[2,3-b]pyrazine-related moiety. Up to now, there is still no report about the total synthesis, structural modification and structural-activity relationship (SAR) study of hyrtioseragamine B. In our previous study, hyrtioseragamine B was subjected to virtual screening and the first preliminary structural modification on furo[2,3-b]pyrazine core was carried out, resulting in the production of derivative Hit-1. This compound showed moderate to strong inhibitory activity against b-secretase 1 (BACE-1) and acetylcholinesterase (AChE), and neuroprotective effect against hydrogenperoxide (H2O2)-induced nerve injury in SH-SY5Y cells. These results indicated that the compounds derived from hyrtioseragamine B was worth to be studied further as novel multi-target anti-Alzheimer’s disease agents. More importantly, the BACE-1/AChE dual inhibitor derived from marine resource is extremely rare. In this project, hyrtioseragamine B will be total synthesized and structural modified by the combination of Organic Chemistry, Medicinal Chemistry and Computer-Aided Drug Design to yield a series of hyrtioseragamin B derivatives, which will be subjected to detailed biological evaluation, including in vitro BACE-1 and AChE inhibitory activity, neuroprotective activity and SAR study as well . The results obtained in this project will provide useful information for the research and development of novel multi-target anti-AD drugs.

Hyrtioseragamine B是从自然界中分离得到的首个具有呋喃[2,3-b]吡嗪母核的新骨架海洋天然产物，目前尚无其合成、结构修饰及构效关系研究报道。申请人前期对Hyrtioseragamine B进行了虚拟筛选和初步结构改造得到衍生物Hit-1。结果表明，Hit-1对BACE-1和AChE具有中等到强抑制活性且具有神经保护作用，是一个新型多靶向抗AD药物模型化合物，值得深入研究。值得一提的是，目前基于海洋来源的BACE-1/AChE双重抑制剂极为罕见。基于此，本课题拟在前期研究基础上利用有机化学、药物化学及计算机辅助药物设计方法，对hyrtioseragamine B开展全合成和多位点合理结构修饰，设计并合成一系列基于hyrtioseragamine B分子骨架的结构衍生物，对其进行详细的抗AD生物活性筛选及构效关系研究，研究成果将有助于发现海洋来源的新型多靶向抗AD药物先导物。

海洋天然产物hyrtioseragamine B是首个具有呋喃[2,3-b]吡嗪片段的新骨架化合物，分子对接表明该化合物可能具有潜在的AChE和BACE-1抑制活性，可作为抗AD先导化合物。因此，本项目对hyrtioseragamine B的合成、结构修饰及其多靶向抗阿尔茨海默症构效关系研究。.首先采用有机化学切断法和生物合成假设途径这两种逆合成分析方法对hyrtioseragamine B的全合成进行了剖析以及关键片段的合成方法学研究。另外，对该分子的药效片段进行结构修饰并将其进行多个与阿尔茨海默症（AD）相关靶点（如乙酰胆碱酯酶AChE、丁酰胆碱酯酶BChE、β-分泌酶BACE-1、淀粉样蛋白Aβ）抑制活性和神经保护研究。对其喹啉片段进行了合成、结构修饰和抗AD活性研究，发现其具有抑制Aβ活性并对Aβ诱导的神经细胞SH-SY5Y损伤具有较好的保护作用；对其呋喃[2,3-b]吡嗪片段进行了结构修饰，采用骨架跃迁的方法合成了一类兼有BChE抑制活性和神经保护作用的香豆素类结构衍生物，以及一类AChE抑制剂。另外，在本项目的资助下，对其他海域来源的AChE抑制剂进行全合成与活性研究、采用计算机虚拟筛选等发现对本实验室以及SPECS商业化合物进行了虚拟筛选、合成与结构优化，发现了多个具有潜在抗AD活性的AChE抑制剂、BChE抑制剂和Aβ聚集抑制剂。另外，在本项目资助下开展了Keap1-Nrf2抑制剂的发现研究和基于海洋吲哚-1,2,4-二恶唑结构衍生物的合成与活性研究。在本课题的资助下，课题负责人以第一或者通讯作者身份发表了包括J Enzyme Inhibit Med Chem, Bioorg Med Chem Letter, Bioorg Chem在内基金标准SCI论文10篇，申请专利4项，其中获得授权专利2项。