Synthesis And Pharmacological Activity Evaluation Of Arctigenin Derivatives

Fructus Arctii,is belong to the plant(Arctium lappa L.)of Asteraceae,Arctium L,which is the dried and ripe fruits.In China,it’s widely distributed in many provinces being as abundant natural resources,and the better quality of Fructus Arctii was produced in northeastern area.The main chemical constituents of Fructus Arctii are lignan,terpenoids and volatile oil,et al.The theory of traditional Chinese medicine research shows that Fructus Arctii dispelling wind and heat,and detoxication,releving swelling activities,et al.Modern pharmacological studies show that Fructus Arctii possesses hypoglycemic,antiviral and hepatoprotective effects and whose main active ingredient is arctigenin.Arctigenin possesses anti-inflammation,anti-colitis,anti-cancer,blood vessels protection and memory protection and so on.The research on pharmacological activity of arctigenin(ARG)has gradually become a hot field.In order to facilitate the application of arctigenin in clinical treatment,present researches have mainly focused on structural transformation of ARG,which is aimed to enhance its activity in vivo.In this context,arctigenin was precursors and synthesized with different carboxylic acids,and the activities of the derivatives were compared with arctigenin.Effects of the synthesized derivatives were investigated through different assays,including anti-bacteriaassay,inhibition on α-glucosidase and acetylcholinesterase assays,and the scavenging on nitrite assay.The more active compounds were screed to investigate their anti-tumor activity.The main research contents of the context were shown as follows:(1)Arctigenin derivatives were prepared according to the esterification reaction using EDCI(decarboxylation agent),DMAP(catalyst),arctigenin was as a precursor and synthesized with different carboxylic acids with esterification synthesis.Finally,24 compounds were successfully synthesized and identified by TLC layer chromatography and NMR spectroscopy of 13 C and 1H NMR analysis.(2)The in vitro anti-bacteria activity of arctigenin and its derivatives were investigated by filter paper method.Among them,sorbate,3,5-dinitrobenzoate and isonicotinate showed inhibitory effect on Staphylococcus aureus;sorbate,thiophene-2-carboxylate,isonicotinate,furoate and 3,5-dinitrobenzoate showed inhibitory effect on Escherichia coli;1-adamantane carboxylic acid ester showed inhibitory effect on Salmonella.(3)The inhibitory activity of 14 derivatives was enhanced than arctigenin in α-glucosidase inhibitory assay,such as arctigenin-2-naphthyl formate,α-lipoic acid ester,myristate,succinic anhydride diester,cinnamate and 3,5-dinitrobenzoate,and so on.(4)The inhibitory activity of 17 derivatives was enhanced than arctigenin in acetylcholinesterase inhibition experiment,their activities in scendingorder are arctigenin stearate,docosyl ester,cinnamate,cinnamate,arachidonic acid ester and sorbate etc..(5)The model of sulfonic acid-ethylenediamine hydrochloride was used to investigate the inhibition effects of ARG and its derivatives on nitrite scavenging assay.The scavenging activity of 14 derivatives was enhanced than arctigenin in nitrite scavenging assay,such as arctigenin-β-indoxyl acetate,succinic anhydride diester,and isonicotinate,and so on.(6)According to the results of nitrite scavenging assay,three derivatives were chose to investigate their anti-tumor activity in vivo.The tumor model of H22 tumor bearing mice was used to investigate the in vivo anti-tumor activity of derivatives through a series of indexes,including thymus index,spleen index,aspartate aminotransferase(AST),alanine aminotransferase(ALT),urea nitrogen(BUN),creatinine(Cre),tumor necrosis factor α(TNF-α),interleukin-2(IL-2),interleukin-6(IL-6),vascular endothelial growth factor(VEGF),H&E staining of tumor tissue and spleen;TUNEL assay,immunohistochemistry of BAX,Bcl-2,VEGF and caspase-3.The inhibitory effect on tumor bearing mice showed that the three derivatives,arctigenin-β-indoxyl acetate,succinic anhydride diester,and isonicotinate,enhanced the anti-tumor activity of arctigenin,with little toxicity.Integrate the activities screening assay in vitro,the activity of arctigenin was enhanced after esterification with a series acids,including isonicotinic acid,nicotinic acid,indoleacetic acid,2-naphthoic acid,benzoic acid,two 3,5 Nitrobenzoic Acid,lauric acid,palmitic acid,and so on.The results indicated the chemical structures transformation could improve the activity of arctigenin.Furthermore,the enhance of anti-tumor activity in vivo provide certain theoretical basis in improving clinical application.