Synthesis And Antitumor Activity Of Oleanolic Acid A Ring And C-28 Derivative

Oleanolic Acid（OA）is a natural pentacyclic triterpenoid compound,which has a variety of pharmacological activities（such as liver protection,anti-cancer）.In recent years,the structural modification and activity of c-3 and C-28 in oleanolic acid A ring have been studied.PDGF belongs to the vascular endothelial growth factor family and is highly expressed in lung cancer,gastric cancer and other tumors.Targeted PDGF receptor inhibitors can inhibit the expression of vascular endothelial growth factor in tumor cells and play an anti-tumor role.In recent years,the anti-tumor effects of pentacyclic triterpenes have been studied deeply and found to be remarkable.Therefore,a novel design idea combining pentacyclic triterpenoids in traditional drugs with PDGF target was proposed in this thesis.In this thesis,computer aided drug design technology was used to analyze the amino acid residues of target proteins and determine the active groups at their binding sites.A series of oleanolic acid derivatives were designed by using oleanolic acid as the lead compound,and benzohydrazyl group was innovatively introduced into its A ring,while ester group and amide group were introduced into C-28 through esterification reaction and amidation reaction.PDGF was used as the target,combined with the THREE-DIMENSIONAL crystal structure（1SHA）of PDGF protein in PDB database,PDGF was simulated with known active small molecules,and two compounds,ten were screened out.TLC was used to monitor the reaction endpoint during the reaction process,and the crude product was separated and purified by column chromatography.None of the compounds have been reported and their structures have been confirmed by ¹H NMR.In this study,MTT assay was used to test the antitumor activity of oleanolic acid derivatives in vitro by using human gastric cancer cell SGC7901 and human lung cancer cell A549 as target cells and sorafenib as positive control drug.The IC₅₀values of compounds I-3 and II-1 against SGC7901 and 8.94μmol·L-1 against A549 were9.28μmol·L-1 and 8.22μmol·L-1,respectively.The antitumor activity of the two compounds was significantly higher than that of maternal oleanolic acid,and superior to the marketed drug Sorafenib.