Optimization Of Synthetic Route Of Ca²⁺ Release Activated Ca²⁺ Channel Retardant YZ54 And Study Of Its Derivatives And Study Of Deuterium Bioluminescent System

Autoimmune diseases such as lupus erythematosus,rheumatoid arthritis,dermatomycosis and autoimmune hemolytic anemia seriously affect the quality of life of patients,traditional immunosuppressive agent(such as glucocorticoid,cyclosporine,tacrolimus,etc.)can control the disease,but the side effects are more serious.Therefore,it is urgent to develop safe and effective immunosuppressive agent for new drug treatment targets.Ca2+ release activated Ca2+ channel(CRAC)is a novel drug target for the treatment of autoimmune diseases and tumor,and its specific blocker has the potential to selectively suppress abnormal immune reaction,and without the toxicity induced by the traditionally immunosuppressive agent,therefore,providing a safe and effective treatment strategy for the treatment of autoimmune diseases.In our preliminary results,we got a good lead compound,YZ54,with reasonable CRAC channel block activity and cell immunity activity.In this thesis,the synthetic process of YZ54 was well optimized,and a new synthetic route of YZ54 was designed.This optimized route had simple steps,mild reaction conditions,and the high total yield up to 31%.Based on the core structure of YZ54,eight isothiourea derivatives as CRAC channel blockers where well designed and evaluated to find the new CRAC channel blockers.In the second part,the effect of deuterium substitution on bioluminescence system is studied.Deuterium,or heavy hydrogen,can invole in forming carbon-deuterium bond,which is stronger than carbon-hydrogen bond.In many cases,carbon-deuterium bond can change the metabolic rate because this bond is broken down slowly by enzyme.Bioluminescent imaging technology has the advantages of high specificity and sensitivity,however,there are several disadvantages in bioluminescent imaging,including short bioluminescent wavelength,low bioluminescent duration,and low sensitivity in deep imaging.To prolong the bioluminescent time in vivo,we modified cybluc,a modified substrate of luciferase with strong bioluminescent signal,to provide d4-cybluc by deuterium substitution.Biological experiments in vivo and in vitro exhibited that the bioluminescent time of d4-cybluc is longer than cybluc.