Design,Synthesis And Biological Evaluation Of Small Molecules That Target Misfolding Amylin

Diabetes mellitus is a metabolic disease characterized by an increase in chronic blood glucose levels due to insulin secretion and functional defects.With persistent high blood glucose as the basic biochemical characteristics,diabetes bring many side effects and diseases to the human body,which cause a variety of inflammatory diseases and even reduce the body’s defenses to tumor cells,the harm is thought to be second to cardio-cerebrovascular disease and malignant tumor.Diabetes is generally divided into four types according to the pathogenesis,the common type includes type 1 and type 2,with type 2 diabetes(T2DM),accounting for more than 90% of the total number of patients with diabetes.The basic characteristics of type 2 diabetes are: the sensitivity of insulin decreases,and the function of islet was impaired.The study of type 2 diabetes mellitus(T2DM)found that about 95% of the patients’ islet tissue showed the deposition of amyloid protein.Protein misfolding and subsequent precipitation is the main reason for the formation of protein precipitation,like amyloid protein in alzheimer’s disease,mad cow disease in the collagen(also called prions),etc.In 1987,Garth JS Cooper,he successfully identified amylin’s main ingredients from diabetes patients’ islet amyloid deposits,which include 37 amino acid residues and is also called islet amyloid polypeptide(IAPP).The pancreatic hormone(amylin)amyloid is formed by destructing pancreatic islet beta cell membrane structure,inducting apoptosis of beta cell and damaging the function of beta cell,which is considered to be one of the most important causes of type II diabetes.Amylin has become a promising target in the treatment of diabetes.Preliminary results have showed that rutin and quercetin of flavonoids had certain inhibitory effects on amylin’s aggregation.But as a result of the weak activity of rutin and quercetin,the project will be studied by our medicinal chemistry research team,using rational drug design strategy on rutin and quercetin as well as explorating and optimizing active pharmacophore,looking for a new type of amylin inhibitors on anti-diabetes drugs research.On the basis synthesis study of rutin and quercetin,we have discovered other compounds that have potent inhibition of amylin,therefore,we work on several lead compounds to design further molecules as inhibitors.