Synthesis And Anti-inflammatory Activity Of Hyodeoxycholic Acid Analogs

Hyodeoxycholic acid is a cheap and easily available natural steroid with a wide range of pharmacological activities.In this dissertation a series of novel hyodeoxycholic acid analogs containing a sulfoxide,sulfone or sulfonimide group were synthesized,and their anti-inflammatory activity were preliminarily evaluated.The dissertation consists of four chapters.In chapter one,the progress on the synthesis of steroidal drugs or steroidal derivatives used the hyodeoxycholic acid as the starting material,and the study on the biological activities of some representative compounds with a sulfoxide,sulfone or sulfonimide group was summarized.In chapter two,we developed a route for the synthesis of some novel hyodeoxycholic acid analogs starting from hyodeoxycholic acid by inducing sulfoxide,sulfone or sulfonimide group on its A-ring,B-ring or the side chain.61 new steroidal derivatives,including 22 target hyodeoxycholic acid analogs were synthesized and their structures were characterized by NMR,HRMS and X-ray.In chapter three,the LPS-induced microglia cell（BV-2）was used as the inflammatory cell model to preliminarily evaluate the anti-inflammatory activities of the target hyodeoxycholic acid analogs.Cell viability was first measured by MTT assay to determine their cytotoxicity.Then the ability to inhibit the NO release of the compounds with low cytotoxicity were further investigated on the LPS-induced BV-2 cell by Griess method.The results indicated that most of the tested could efficiently inhibit the production of NO in BV-2 cell.Two most promising compounds 10 b and 20 a were selected to further elucidate their anti-inflammatory potency and action mechanism via morphology analysis,WB assay and immunofluorescence test.The results indicated that compound 20 a could significantly inhibit the formation of the pro-inflammatory M1 morphology in LPS-induced BV-2 cell and promote them to convert to the anti-inflammatory M2 morphology.Compounds 10 b and 20 a also could down-regulate the express of TLR-4 receptor in a dose dependent manner,inhibiting the phosphorylation of the IκB kinase to deactivate the NF-κB signal pathway to exert their anti-inflammation.In chapter four,the main research contents of this dissertation was summarized.