Synthesis And Antitumor Activity Of ?-hederin Derivates

Saponins are a vast group of naturally occurring plant glycosides,characterized by their strong foam-forming properties in aqueous solution.Sapomins are the key ingredients of traditional Chinese medicines and other folk medicines worldwide,with diverse biological effects including anti-tumor,anti-inflamatory,anti-diabetic and anti-fungal functions.Among them,oleanane-type saponins such as oleanolic acid 3-O-?-Lrhamnopyranosyl(1?2)-?-L-arabinopyranoside(?-hederin)and its derivates from Ivy,Pulsatilla chinensis and Patrinia scabiosaefolia have drawn considerable attention due to their strong anti-tumor activities.Chemical compounds isolated from special plant are generally limited company with tedious work.Semi-synthesis of these complex saponins has been an efficient way to explore their antitumor structure-activity relationship.In recent years,we have been devoted to discovering pharmacologically anticancer agents.Previous studies on isolation and synthesis of these regents have revealed ?-hederin as potential antitumor agents,as well as its hemolysis activity.In this thesis,using principle of prodrug,we have designed and synthesize a set of ?-hederin 28-esters to explore its antitumor/ hemolysis structure-activity relationship.Staring with oleanolic acid,the 28-carboxyl group was protected by benzyl group at first.Benzyl oleanolate intermediate,oleanolic acid 3-O-2??,3??,4??-tri-benzoyl-?-Lrhamnopyranosyl(1?2)-3??,4??-diacetyl-?-L-arabinopyranosyl-28-O-benzyl ester(17)was connected with arabinopyranosyl followd by rhamnopyranosyl group by two-steps glycosidation.Benzyl group was then removed to afford 28-COOH intermediate,followed by glycosidation and esterification.Finally,the protective group was removed to give 9 compounds respectively as follows with good yield: ?-hederin(1),oleanolic acid 3 – O-?-L-rhamnopyranosyl(1? 2)-?-L-arabinopyranosyl-28-O-?-L-arabinopyranoside(2),oleanolic acid 3-O-?-L-rhamnopyranosyl-(1?2)-?-L-arabinopyranosyl-28-O-?-L-rhamnopyranoside(3),oleanolic acid 3-O-?-L-rhamnopyranosyl(1?2)-?-Larabinopyranosyl – 28-O-?-D-glucopyranoside(4),oleanolic acid 3 – O – ? – L-rhamnopyranosyl-(1?2)-?-L-arabinopyranosyl-28-O-ethyl ester(5),oleanolic acid 3-O-?-L-rhamnopyranosyl-(1?2)-?-L-arabinopyranosyl-28-O-hexyl ester(6),oleanolic acid 3-O-?-L-rhamnopyranosyl-(1?2)-?-L-arabinopyranosyl-28-O-octyl ester(7),oleanolic acid 3-O-?-L-rhamnopyranosyl-(1?2)-?-L-arabinopyranosyl-28-O-sixteen alkyl ester ester(8),and oleanolic acid 3-O-?-L-rhamnopyranosyl-(1?2)-?-L-arabinopyranosyl-28-O-benzyl ester(9).Their structures are all confirmed by ESI-MS and NMR.The antiproliferation effects of compounds 1~9 were assessed using MTT assay in vitro.Three human cancer cell lines,HELA,HePG2 and A549 were tested with normal cell line 293 T as reference.The hemolytic test of compounds 1~9 were assessed by spectrophotography method,using rabbit red cell in vitro.By comparisons with those of ?-hederin(1),the primary results showed that:(1)as for monoglycoside esters,compounds 2~4 remained inhibition activites to some content,with 4 as better one;(2)as for alkyl and benzyl esters,compounds 5 and 6 remained inhibition activites to some content,while 7~9 showed no activities possibly due to poor water solubilities;(3)compounds 5~9 showed no activities,while 2~4 showed little hemolysis rates(4.0-5.2%)at 25 ?g/mL.Taken together,these results indicate that ?-hederin esters 2~6 remain antitumor activities with little showed little hemolysis,which need further tests in vivo.