阿尔茨海默症(AD)是继心脑血管疾病和癌症后的人类“第三大杀手”，且无特效治疗药物。神经生长因子(NGF)能够促进神经生长、分化，目前已用于AD等神经系统疾病的临床试验，但由于其蛋白质的理化性质及昂贵的费用等原因，临床应用受到限制。因此，从天然产物中寻找促神经分化的小分子化合物具有重要意义。我们前期从印度洋深海沉积泥来源产黄青霉菌的次级代谢产物中分离得到15个新的硝基苯反式环氧酰胺类化合物，部分化合物具有明显的促神经分化活性，初步作用机制研究表明该类成分促神经分化活性可能是通过CaMKII、PI3K/Akt和MEK/ERK这几条信号通路介导的。本项目拟在前期工作基础上，结合HPLC-HRESIMS和OSMAC策略快速检识和富集硝基苯反式环氧酰胺类化合物，评价其促神经分化的活性，阐明其作用机理和构效关系，以期发现2-3个结构新颖、活性良好的抗AD新药先导化合物。

Alzheimer's disease (AD) affects human health but its etiology and pathogenesis are not clear and there are no specific drugs. NGF can promote the central and peripheral nerve growth, differentiation and survival, which has been developed for the treatment of AD. However, some protein natures of NGF limit it to be an ideal clinical medicine. As a result, it is important to discover small molecule drugs with nerve cell differentiation activity for the treatment of AD. Our previous study on the deep-sea-derived Fungus Penicillium chrysogenum SCSIO41001 had led to the isolation of 15 new nitrophenyl trans-epoxyamides, some of which had induced the neuronal differentiation and activated CaMKII, PI3K/Akt and MEK/ERK. On the basis of preliminary work, the project aims to the thorough chemical research of nitrophenyl trans-epoxyamides from Penicillium chrysogenum SCSIO41001 by the strategies of HPLC-HRESIMS and OSMAC. The activities of inducing nerve cell differentiation together with the mechanism and structure-activity relationship of these compounds will be further evaluated. It is supposed to discover 2-3 lead compounds with novel structures and good activities for the treatment of AD.