Study On The Modification And Transformation Of The Structure Of Bergenin Lactone Ring

Immunosuppressive agents have an inhibitory effect on the immune response of the body,which can not only inhibit the proliferation of immune response-related cells such as T cells and B cells,but also reduce the frequency of the immune response.Clinical immunosuppressive agents are mainly used for organ-transplant anti-rejection and autoimmune diseases such as rheumatoid arthritis,lupus erythematosus,skin fungal disease,membranous glomerulonephritis,inflammatory bowel disease and autoimmune hemolytic anemia etc.The main immunosuppressive agents currently used in clinical application,such as cyclosporine A,tacrolimus,cyclophosphamide,tripterygium,generate broad and potent immunosuppressive effects accompanied with some frequent side effects which sometimes are even fatal,so it is necessary to search for more efficient and low toxicity immunosuppressive agents.Bergenin is a class of isocoumarin compounds isolated from plants with a variety of biological activities,which is a tricyclic ?-C-glycoside made up of 4-methylated gallic acid and glucose.It occured to us that bergennin can act as substrate to be modified through rational drug design,where we would be able to obtain new compounds with low toxicity and high immunosuppressive activity.In this paper,based on the experience of immunosuppressive agents in our group and the results of biological activity assay of the existing bergenin derivatives,two series of bergenin derived compounds were designed,which contain lactone ring-opening modification and lactone ring transformation.The six-membered lactone ring opening modified moieties include amination modification of the primary hydroxyl groups,alkylation modification,modification of the secondary hydroxyl group at 4a-position and so on.The transformation of the six-membered lactone ring includes the conversion of the six-membered lactone ring into a six-membered lactam structure,a six-membered ether ring structure,a six-membered hemiacetal ring structure,a seven-membered ring structure containing a carbamate and so on.The synthesis process involves the selective protection of functional groups,the redox reduction of hydroxyl groups,the lactone ring-opening reaction,the lactone ring ammonolysis reaction and Curtius rearrangement reaction etc.A total of 15 target compounds were synthesized,where 32 new compounds were obtained during thesynthesis process.