Design,Synthesis And Bioactivity Evaluation Of DJ-1 Protein Inhibitors,and Synthesis Of Indole[2,1-α] Isoquinoline Derivatives

DJ-1 protein is a multifunctional protein against oxidative stress,which has neuroprotective function associated with neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.At the same time,DJ-1 is also recognized as a tumor factor,which is overexpressed in a variety of tumor cells and promotes the proliferation of tumor cells.Effectively inhibiting the biological cytoprotective function of DJ-1 may be a new way of tumor treatment.Studies have shown that DJ-1 protein has glyoxalase activity,which is suitable for classical enzymatic analysis.The inhibitory efficacy of compounds on DJ-1 protein can be determined by glyoxalase activity.However,the lack of effective DJ-1 inhibitor research limits the deep understanding of the anti-tumor physiological function of DJ-1,thus confirming that DJ-1 is an anti-tumor drug target lacks a certain theoretical basis and material basis.Based on the previous research,this thesis firstly carried out the design and synthesis of DJ-1 protein inhibitor.According to the co-crystal structure of DJ-1 with its covalently bound inhibitor,we designed and synthesized 29 compounds including isatins and α-chlorine lactams by using structure-based drug molecule design method and combining medicinal chemistry knowledge.The compounds were tested to inhibit DJ-1 protein glyoxalase activity,and the results showed that some compounds had higher inhibitory activity on DJ-1 protein than the positive control,which provided a theoretical and material basis for the study of DJ-1 protein ligands.In addition,a facile and efficient protocol for the synthesis of indole[2,1α]isoquinoline derivatives via the reaction of 2-aryl-N-acryloyl indoles with aryl or alkyl α-keto acids was developed.Indole[2,1-α]isoquinoline structures widely exist in biologically active compounds or drug molecular structures,and are widely demanded in medicinal chemical synthesis.The synthesis method has mild reaction conditions,does not require metal catalyst participation and has a wide substrate range and good functional group tolerance.Based on a series of control experiments,we proposed a free radical mechanism to explain the reaction.Compared with the methods for synthesizing indole[2,1-α]isoquinoline derivatives proposed in the past,the method has shorter reaction time and simpler and more economical operation.