Synthesis,Characterization And Anti-inflammatory Evaluation Of Hesperetin-7-ether Derivatives

Natural products have always been an important source of drugs and precursor compounds.Natural products have the characteristic of diversity and complex chemical structure,kinds of biological activity.Previously,synthetic drugs not only have more side effects and drug resistance,but also cause many drug-induced diseases.So it is particularly important to the development of natural products.Hesperetin is a kind of flavonoids,which is obtained from the hydrolysis of a moiety of glycosides in hesperedin.Both of them are flavanones.Hesperetin and hesperedin are mainly derived from the peel of the citrus fruit,which are the main active ingredients in the citrus peel.It was also found in many fruits,vegetables,tea and beans.It was investigated that hesperetin has a lot of pharmacological properties,such as anti-inflammation,anti-oxidation,anti-allergy,anti-tumor,immune system enhancement,anti-radiation,antibacterial and anti-virus,protection of cardiovascular system and so on.Although its pharmacological activity is widespread,it also has the properties of poor water solubility and fat solubility,easy to be metabolized in the body,which means difficult to maintain high drug concentration.Such a low bioavailability limit the clinical application.It have been proved that the biological activities remarkably depend on compounds' structural characteristics.Our laboratory previously synthesized a series of hesperetin derivatives,and found that some of them show a better anti-inflammatory activity than hesperetin.5,7,3'-triacetyl hesperetin could suppress adjuvant-induced arthritis(AA)in rats through modulating JAK2/STAT3 pathway,while 7,3'-dimethoxy hesperetin inhibited inflammation by inducing synovial apoptosis in AA rats.Hesperetin derivative-7 inhibited the activation and proliferation of PDGF-BB-induced HSC-T6 and attenuated liver fibrosis through targeting the Wnt/?-catenin signaling pathway,while hesperetin derivative 11 suppressed hepatic stellate cell activation and proliferation by targeting PTEN/AKT pathway.To explore new drug resources and expand the utility of hesperetin,we continued to modify the structure of hesperetin and expected to find better activity of hesperetin derivatives.The detailed contents of the research are as follows:1.Synthesis of 7-ether hesperetin derivatives: The substituted of hesperetin 7-hydroxyl group changes their stereostructure,oil-water partition coefficient and activity.The sixteen derivatives were prepared by hrsperetin reacting with different brominated aryl and alkyl.Their in vitro anti-inflammatory structure-activity relationship was analyzed.2.In vitro anti-inflammatory experiments: We carried out the experiment by the LPS stimulated RAW 264.7 macrophage cell line of novel hesperetin derivatives.There were three groups: normal group,LPS group,and experiment group,and obtained the inhibitory activity on expression of IL-1? and IL-6,and production of NO.From the result,compound 1f,1h,1i,1l and 1k can obviously inhibit the production of NO,while compound 1d,1h,1k,1l,2a,2b and 2c can reduce the secretion of IL-1? and IL-6.All above compounds show a better activity than hesperetin.3.Expression of proteins: The most potential compound 1l was chosen to explore the influence of the associated inflammatory protein.It was found that compound 1l can alleviate the expression of i NOS and activation of NF-?B.4.In vivo anti-inflammatory effect of compound 1l: Effect of compound 1l in CCl4-induced acute liver injury mice was carried out in six groups: normal group,model group,compound 1l treatment group(50 mg/kg,100 mg/kg,200 mg/kg),and Silymarin group(200 mg/kg).The result indicated that compound 1l can relieve liver injury and lower the level of IL-1? and IL-6.