Design,synthesis And Anti-inflammatory Activity Of Dihydroflavonol Derivatives

Dihydroflavonols as a kind of important natural products,which are widely found in natural plants,modern research shows that dihydroflavonols have many biological activities,such as antioxidant,anti-inflammatory,antitumor and antivirus.In this paper,on the basis of the results of previous studies,we use the anti-inflammatory gynecological active ingredients as the research object,and choose the best anti-inflammatory dihydroflavonol component namely taxifolin as the lead compounds,the different series of the dihydroflavonol derivatives are synthesized,and their anti-inflammatory activity and the structure-activity relationship were studied.The purpose of this study is to find the new dihydroflavonol which have higher anti-inflammatory activity,provide lead compounds for the study of the new anti-inflammatory drugs,and provide substantial theoretical basis for further structural optimization and drug development.Through the research,this experiment has obtained the following main results:1.In this paper,a new route for the synthesis of dihydroflavonol derivatives was studied by consulting a large number of literatures:A series of dihydroflavonol derivatives were synthesized by the reaction of2’-hydroxyl chalcone derivatives with H₂O₂/（CH₃）₂NH system in anhydrous THF under the condition of low temperature The influences of reaction temperature,reaction solvents,the kind and proportion of alkaline catalyst and oxidant kinds and proportion on this reaction were investigated,and the optimal reaction conditions were determined.This method has the advantages of simple operation,mild conditions and convenient post-treatment.The method has the advantages of simple operation,mild condition and convenient treatment,which provides a new idea for further industrial production of dihydroflavonol derivatives.2.30 dihydroflavonol derivatives were designed and synthesized,using taxifolin as the lead compound,and through nuclear magnetic resonance（NMR）and its structure was characterized by.In addition,circular dichroism（CD）data showed that the synthesized derivatives were the two configurations-trans（2R,3R）and（2S,3S）3.The mouse macrophages（RAW264.7）were used as the model cells,whereafter the cytotoxicity of all dihydroflavonol derivatives and the effects of LPS-induced release IL-1β,IL-6 and TNF-αon RAW264.7cells were determined.First,the MTT method was used to select 7 drug concentrations,and the results showed that all the derivatives did not show significant cytotoxicity at the concentration of 20μM.Second,according to the results of cytotoxicity,the concentration of drug was determined to be 20μM.The inhibitory effects of LPS-induced on RAW264.7 release inflammatory factors were determined.The results showed that most of dihydroflavonol derivatives could have inhibitory effect,meanwhile,the compounds D9,D13,D19 showed a better inhibitory effect than taxifolin.4.Based on the analysis of the data obtained from the anti-inflammatory activity research,the anti-inflammatory activity relationship of dihydroflavonol derivatives was obtained.The effect of the structure of the B ring on the anti-inflammatory activity was significant,and the activity of the B ring was enhanced when its 4’was replaced by fluorine atom.At the same time,when the B ring is modified for pyridine ring,the anti-inflammatory activity was significantly enhanced.The structure of the A ring was important for the anti-inflammatory activity,and the phenolic hydroxyl group of 5,7 was necessary for anti-inflammatory activity,and a phenolic hydroxyl was added to the 6 position of the A ring,and the anti-inflammatory activity was enhanced.The C ring structure of dihydroflavonol derivatives is an essential structure for its anti-inflammatory effect,and the structural modification of C ring can reduce its anti-inflammatory activity.To sum up,the research of this paper is of great significance for the development of a new type of dihydroflavonol anti-inflammatory drugs.In particular,compounds D9,D13,and D19 showed excellent inhibitory effects on inflammatory factors.These highly active dihydroflavonol derivatives can be used as the leading compounds of anti-inflammatory drugs.