Design, Synthesis And Neuroprotective Studies Of Piperlongumine Analogues

Normal levels of reactive oxygen species(ROS) play a key role in maintaining numerous physiological functions. However, oxidative stress induced by excessive ROS can impair many cellular components, which leads to the occurrence of diverse diseases. Research shows that oxidative stress and neurodegenerative diseases are closely related, and the cellular antioxidant system can block or delay the occurrence of this kind of disease. Thus compounds that can enhance endogenous antioxidant defense capabilities are expected to be potential neuroprotective agents. Piperlongumine is a popular natural product with a variety of biological and pharmacological activities and attracts lots of researchers to study its biological functions. In this thesis, We designed and synthesized a series of piperlongumine analogues, studied their neuroprotective activity, mechanism of action and structure-activity relationship(SAR). The main contents are summaried as follwings:1. A brief introduction of neurodegenerative diseases and antioxidant defense system was presented. We then introduced the Keap1-Nrf2-ARE signaling pathway, the mechanism of antioxidant and the research progress of Nrf2 activators. In additon, the piperlongumine were introduced, including its origin, biological and pharmacological activity, preparation and chemical modification.2. A series of piperlongumine analogues were prepared and their cytoprotective abilities against hydrogen peroxide- and 6-hydroxydopamine-induced neuronal cell damage were evaluated. In initial screening, the cytotoxicity and the protection of these compunds to were determined in PC12 cells, the SAR was also disclosed. Next, we selected compounds 4 and 5 for the follow-up studies as they have lower cytotoxity and better protection, the results showed that both of them can effectively protect PC12 cells from oxidative damage by upregulating the level of intracellular antioxidants. After silencing the transcription factor Nrf2 which is a major regulator of the cellur antioxidant responses, the cell protection function of compound 4 and 5 are greatly decreased, indicating the involvement of Nrf2 for the cytoprotection of 4 and 5. The research work of this thesis will provide guidance for the further modification of piperlongumine and design of neuroprotective molecules.