Design,Synthesis And Anticancer Activity Study Of Derivatives Of 18?-glycyrrhetinic Acid And Oleanolic Acid

Cancer has become a leading cause of death in humans.Therefore,in recent decades,researchers in the field of medicine have been actively studying cancer and trying to develop drugs with high anticancer activity.The study found that,through the structural modification of natural products with anti-cancer activity,which is easy to get low toxicity,high efficiency anticancer drugs.Glycyrrhiza uralensis Fisch.and Ligustrum lucidum Ait.are nature products,and 18?-glycyrrhetinic acid(18?-GA)and oleanolic acid(OA)as two kinds of natural compounds extracted from them respectively.It has been shown that 18?-GA and OA are similar in structure and belong to the pentacyclic triterpenes,and have certain anti-inflammatory,anti-virus,anti-tumor and other biological activity.Our country is rich in resources of Glycyrrhiza uralensis Fisch.and Liustrum lucidum Ait..So 18?-GA and OA in clinical has been widely used,and their medicinal prospect is very broad.In order to obtain 18?-GA and OA derivatives with high anticancer activity,18?-GA and OA with certain anticancer activity were used as lead compounds.The carboxyl and hydroxyl positions of 18?-GA and OA were structurally modified by splicing principle,and their derivatives were tested for anticancer activity.This thesis mainly includes the following three parts:The first part introduces the pharmacological activities,the research progress and development prospects of 18?-GA and OA.In the second part,a series of derivatives of 18?-GA and OA were designed and synthesized.The esterification of 18?-GA and OA was performed by treatment with ethyl bromide(EtBr)or benzyl bromide(BnBr)to produce ethyl ester or benzyl ester,then the introduction of organic acid groups at the C-3 hydroxyl position of 18?-GA and OA,a total of 30 compounds were synthesized,of which 28 compounds were new compounds,and the new compounds were characterized by high resolution mass spectrometry and NMR.The third part is to study the antitumor activity of 18?-GA and OA and their derivatives by MTT assay.The inhibitory activity of 18?-GA and OA ethyl ester derivatives on breast cancer cells(MCF-7),hepatoma cells(HepG2)and human normal liver cells(LO2)were tested,and the inhibitory activity of 18?-GA and OA benzyl ester derivatives on gastric cancer cells(SGC-7901),hepatoma cells(HepG2),breast cancer cells(MCF-7),cervical cancer cells(HeLa),esophageal cancer cells(Eca-109)and human normal skin fibroblasts(HSF)were tested.The results showed that compounds 5o,5p and 7b showed higher anticancer activity than the commercially available anticancer drug gefitinib.In addition,the study of Hoechst 33342 staining,Annexin V-PE/7-AAD double staining and MDC fluorescence staining showed that compound 7b could induce apoptosis and autophagy in HepG2 cells.