Design,Synthesis And Biological Evaluation Of Ganoderic Acid Analogues As Anti-Osteoporosis And Anti-Inflammatory Agents

Ganoderic acids,Tetracyclic triterpenoids from ganoderma lucidum,have a wide range of biological activities.However,ganodermic acids have some problems,the extremly low content,the difficult extraction and the high market price,which limit the further biological study.Therefore,it is meaningful to make ganoderic acid analogs by chemical synthesis and optimize their structures to obtain drug candidates for related diseases.For anti-osteoporosis,studies have shown that ganoderic acid DM and ganoderic acid F have good anti-osteoporosis activity.While their contents are very low,they are difficult to further study.Ganoderic acid analogues A2 and A3 were screened from our small compound library,which showed moderate activity of anti-osteoclast differentiation.Therefore,we make A2、A3 as the hit coumpounds.Then we chose the commercial deoxycholic acid as the starting material and designed and synthesized 32 ganoderic acids analogues.Finally we test their carry on the antiosteoporosis activity.9 compounds,including A1,A6,B7,B3,B11,B14,B18,B17 and B20 were obtained,which showed good anti-osteoclastic activity(>50%)at 0.1μM concentration.A1 and B11 possess very low cytotoxicity and almost completely inhibit the formation of osteoclasts at 0.1 μM concentration and their inhibition rates were 99.7% and 99.9%,respectively.So,this work provides good lead compounds for the development of new drugs against osteoporosis.For anti-inflammatory,studies have shown that ganoderic acids extracted from Ganoderma lucidum have good anti-inflammatory effect.Therefore,in this thesis,ganoderic acid C2,J,E and their derivatives were designed and synthesized from relatively cheap and abundant ganoderic acid A,and their anti-inflammatory activities were tested.Result showed that the derivatives of ganoderic acid A,Z2-03,Z2-07,Z2-08,Z2-17,Z2-25 and the ganoderic acid J derivative,Z2-23,have better antiinflammatory activity.The Z2-23 possesses the best anti-inflammatory activity and its inhibition rate reached 171.8% at 40 μM.This work provides a good lead compound for the development of anti-inflammatory new drugs.This work of the thesis provides a new idea for the development of antiosteoporosis and anti-inflammatory drugs.