Synthesis And Anti-tumor Activity Of Natural Saponin Albiziabioside A And Its Derivatives

Oleanolic acid saponins(OASs)are a family of natural products widely distributed in plants such as fructus ligustri lucidi,albizia,notoginseng,which own anti-tumor,immune regulation,anti-viral,anti-inflammatory,regulation of blood sugar level,prevention of cardiovascular disease,hepatoprotection,fatigue resistance,and many other pharmacological effects and biological activity.Based on the summary of the progress on the separation,bioactivity evaluation,chemical synthesis and structure activity relationship study of the naturally anti-tumor OASs,we carried out the project of the medicinal chemistry research of natural saponins Albiziabioside A.Thereafter structure modification of Albiziabioside A was performed to provide four classes of derivatives.The results of examination on their antitumor activity in vitro and in vivo disclosed some new information of this class of saponin with potential use as antitumor agent in further devleopment.This dissertation was started from the chemical synthesis of albiziabioside A through a linear synthetic strategy of 10 steps with 12.7%of the overall yield.The synthetic Albiziabioside A exhibited outstanding growth inhibition of six different skin cancer cells with lowest IC50 values(5.47 ?M)for A375 cells.Moreover,Albiziabioside A can induce A375 cell apoptosis via mitochondrial pathways involving a caspase cascade.Six derivitves of series A was designed for the judgment of the contribution of the saccharide moiety to the activity.Compared with Albiziabioside A,this series of compounds presented less antitumor activity,which proved the important role of the arabinose moiety.Next,total ten compounds of series B were synthesized under the direction of replacement of the acetyl group on albiziabioside A by various aroma or fatty acyl groups.Most of these compounds showed stronger proliferation inhibition against tumor cells,and obvious structure-activity relationship was concluded accordingly.In view of compound B10 with cinnamon acyl group presenting good selectivity,we designed and synthesized series C compounds,which were the derivitives of albiziabioside A coupled with diverse substituentially cinnamoyl groups.This seires of compounds showed excellent properties both on activity and selectivity.Typically,compound C13 was the most promising derivative,and in addition it showed lowertoxicity against human normal cell line.Further mechanism study indicated that it induces HCT116 cells apoptosis via the mitochondrial pathway.Last,a library of albiziabioside A triazolyl derivatives(series D)modified at C-28 carboxylic position were designed and synthesized by employing 1,3-dipolar cycloaddition strategy.MTT experimental data showed that this modification can significantly increase the antitumor activity of the target compounds.Compound D13 showed highest anticancer activity against HCT116 cells with IC50 value of 5.19 ?M.Further pharmacological experiments showed that compound D13 can induce HCT116 cells apoptosis via mitochondrial pathway.In vivo experiments showed that compound D13 has low toxicity withthe LD50 value above 1000 mg/kg and it can effectively inhibit the tumor growth in mice models.In summary,the forementioned five aspects of researches in this dissertation apply new ideas for the saponin synthesis methods.Meanwhile,the finding of some lead compunds will be beneficial to afford new and significant approach to the development of saponin medicinal chemistry.