SAR Study Of Nuclear Receptor Nur77 Binding Affinity Of Celastrol Derivatives And Methodological Study Of Coupling Reaction Of Celastrol With Phosphite In C6 Position

Nur77,a member of nuclear receptor superfamily,play an important role in the occurrence and development of autoimmune diseases,cancer and many other diseases.Our lab found that a bioactive component from the root bark of traditional Chinese medicine Tripterygium wilfordii called Celastrol,can directly bind to Nur77 to inhibit inflammatory and induce autophagy by promoting Nur77 translocation from the nuclear to mitochondria and interaction with TRAF2.Thus,our lab is interested in optimizing Celastrol as a Nur77-targeted agent for treating disease.The goals of my graduate research are to synthesize a series Celastrol derivatives for the SAR study of their Nur77 binding affinity and to explore the possibility of making novel Celastrol derivatives with intellectual property protection.My research work includes:1)synthesized and characterized 29 Celastrol derivatives with modifications at the C20 and C6 position,and with changes in the Celastrol scaffold.I applied many types of chemistry such as acyl fluorination,glycosylation,phosphitylated,coupling and other reaction types,which have enriched the modification methods of Celastrol;2)investigated the relationship between structure and Nur77 binding affinity of the synthesized Celastrol derivatives,and evaluated the anti-inflammatory activity of these compounds,which provides some important insight for the further optimization of Celastrol;3)We found that derivative XS0486 with a phosphite on C29 position can bind Nur77 well and shows good anti-inflammatory activity.In addition,we developed a coupling method of attaching phosphite group to the C6 position of Celastrol with metal-free catalyst.The coupling reaction proceeds with alkaline conditions as catalyst and dimethyl sulfoxide as solvent under mild conditions and reaction time of 20 minutes.The method has several advantages:1)it does not require harsh reaction condition and anhydrous anaerobic system;2)the catalyst is inexpensive and easy to prepare and store;3)the reaction time is short,about 20 minutes at the room temperature;4)product is single and easy to purify.The reaction has high yield,up to 94%,and is conducive to mass production.