Study On Synthesis And Anti-inflammatory Activity Of Gentiopicroside Derivatives

Natural product Gentiopicroside is a series of iridoid glycosides,has a good anti-inflammatory analgesic effect,in addition,there are liver,gallbladder,stomach,antispasmodic,heat,anti-tumor,anti-oxidation and lower blood pressure and other pharmacological activity.The research group found that gentiopicroside is a novel selective inhibitor of COX-2,but its structure in which the hydrophilic fragment is too strong,leading to reduced oral bioavailability,accelerating metabolism,shortening the half-life,and restricting the effective.This paper starts from the molecular structure of gentiopicroside,its structure modification,by introducing hydrophobic groups appropriately,enhance the liposolubility,design and synthesis of a series of gentiopicroside derivatives,and to evaluate the activities of the derivatives,to select new compounds better anti-inflammatory activity.Based on this,the following two aspects are studied:1.The Synthesis of Gentiopicroside Derivatives Gentiopicroside as the precursor compounds,respectively,the choice of benzaldehyde and other 26 aldehydes compounds,2,2-dimethylpropane and other 10 ketone compounds,so that in the N2 under the protection of CH3 CN as solvent,p-toluenesulfonic acid or 4-methylbenzenesulfonate pyridine as catalyst,heated reflux stirring.Detecting the completion of the reaction by thin layer chromatography,it was isolated and purified by column chromatography,and finally 27 monomer compounds were obtained;And the pyridine were selected as the solvent and acetic anhydride as raw materials,and the mixture was stirred with gentiopicroside at room temperature.Detecting the completion of the reaction by thin layer chromatography and purified by column chromatography to obtain the acetylated product of gentiopicroside.The structures of 28 compounds were characterized by NMR,IR and HR-ESI-MS.The results showed that all the spectral data of 28 newly synthesized compounds were consistent with their structural characteristics,the purity is high,the polarity of the 28 compounds is weaker than gentiopicroside.Finally,the synthesis conditions of each compound were optimized.2.Study on Anti-inflammatory Activity of Gentiopicroside Derivatives The anti-inflammatory activity of 28 new compounds was studied by in vivo and in vitro experiments.In vitro experimental selection of mouse macrophages RAW264.7 as the object,firstly we studied the effects of each compound on the viability of macrophages,secondly,we studied the effects of compounds on the production of NO and the release of inflammatory factors PEG₂ and 1L-6 of macrophages after LPS-induced.The results showed that when the concentration of each derivative was less than 100 ug / m L,macrophage activity was not affected,so choose 100 ug / m L for the maximum concentration of administration;Respectively,to 100,50,25 ug / m L concentration of derivatives acting on LPS-induced macrophages,it was found that the derivatives of P2,P5,P8,P22,P23 and P26 could significantly inhibit the production and release of NO and inflammatory factors PEG₂,1L-6?P <0.05 or 0.01?..In vivo experiments,KM mice were used as the research object,the anti-inflammatory effect of the compounds was determined by ear swelling test.The results showed that P2,P3,P8,P12,P22,P23,P26 and other derivatives had different inhibitory effects on mouse ear swelling?P <0.05 or 0.01?.In combination with in vitro and in vivo experiments,gentiopicroside derivatives with good anti-inflammatory activity such as P2,P8,P22,P23 and P26 were selected.In this paper,through the introduction of hydrophobic groups were structural modification of gentiopicroside,28 novel gentiopicroside derivatives were synthesized,a new compound of gentiopicroside than polarity decreased,lipid solubility enhancement,to achieve the desired purpose,the research found that anti-inflammatory activity,the results showed that some of the gentiopicroside derivatives were higher than those of gentiopicroside,and a group of new compounds with good anti-inflammatory activity were selected.This study provides an experimental basis for the rational development and utilization of the potential anti-inflammatory activity of gentiopicroside and the search for new COX-2 selective inhibitors.The research on the anti-inflammatory mechanism and the selective inhibition of COX-2 on the new gentiopicroside derivatives will be done further.