Synthesis And Anti-inflammatory Activity Of Derivatives Of Dibenzylbutane Lignan LCA From Litsea Cubeba(Lour.) Pers Root

Rheumatoid arthritis?RA?is a chronic systemic autoimmune disease that arises more frequently in females than males and frequently observed in the elderly.It mainly affects the patient's joint synovium.The clinical manifestations are symmetrical joint involvement,including joint pain,swelling,inflammation,accompanied by proliferative synovium,cartilage damage,bone erosion,and systemic consequences.In severe cases,even the patient's functional activities are restricted.Leading to disability,causing financial burden to patients themselves and society.Early detection,early diagnosis,and early treatment are currently more effective treatments.At present,the drugs for clinical treatment of RA mainly include small-molecule drugs:non-steroidal anti-inflammatory drugs?NSAIDs?,glucocorticoids and chemically modified antirheumatic drugs?DMARDS?,etc.However,these drugs have more adverse reactions.Macromolecular biologics,including TNF inhibitors,interleukin receptor inhibitors,and bioinhibitors targeting T and B cells which against the pathogenesis of RA.However,injection is the only way to use these biologicals.Therefore,there are adverse reactions such as severe infections and expensive,so they are used with caution.Therefore,it is necessary and urgent to find new drugs for multi-target and multi-pathway treatment of RA.Researches by Lin Bin and others found that LCA was extracted from the active site of dichloromethane in traditional Chinese medicine from Litsea cubeba?Lour.?Pers root.After experimental research,it has been shown that there is obvious anti-inflammatory activity from LCA.Purpose:To complete the synthesis of the compound with anti-inflammatory activity LCA extracted from Litsea cubeba?Lour.?Pers root,and to find new compounds with higher activity with anti-inflammatory activity;we also synthesized five series of new LCA derivatives,and The structure-effect relationship is discussed.Method:Through the analysis of the LCA structure,the reverse separation of the reverse synthesis was carried out,and two different synthetic routes were designed,one of which was an incompatible synthetic route,after esterification,hydrogenation,benzyl protection,hydrolysis,substitution,etc.The reaction successfully synthesized the target compound.In addition,through the intermediate W₁ of the asymmetric synthesis route and the intermediate W₂ of the symmetric synthesis route,different side chain groups such as primary and secondary aliphatic chains,substituted piperazine,substituted benzylamine and substituted aniline were introduced into the carboxyl groups to synthesize A,B,C,D,E,five types of LCA derivatives,and 27 compounds of the five types of compounds were subjected to cytotoxicity test and LPS stimulated RAW.264.7 cells to produce NO content inhibition test.Results:The cytotoxicity tests showed that in addition to the w-2-17,w-1-57 and w-2-21 in class D compounds,and w-4-2,w-4-14 in class E compounds are at concentrations below 3?M,3?M,15?M,3?M and 15?M have no cytotoxicity,there is no significant effect on cell proliferation during another compound in the tested concentration range.NO inhibition experiment tests showed that the A compound w-1-34 and D compound w-1-61 at 30?M concentration can inhibit the NO content of cells,B compound w-2-17 E compound w-4-18 inhibited the NO content of cells at a concentration of 3?M,while E compound w-4-14 suggested that it inhibited NO at a concentration of 1.5?M in a dose-dependent manner.In summary,5 compounds have anti-inflammatory activity.Simultaneously calculate the IC₅₀ values of 27 compounds.Conclusion:A total of 5 LCA derivatives described above have anti-inflammatory activity.The test show that 4-OCH₃phenylpiperazine introduced w-1-34(IC₅₀=45.49?M)has high anti-inflammatory activity in Class A compounds,and in Class B compounds The anti-inflammatory activity of w-2-17(IC₅₀=1.44?M)introduced with 4-OCH₃ benzylamine was the best.highest activity among the class D compounds is the cyclic imide compound w-1-61(IC₅₀=17.10?M)introduced with 2-OCH₃ aniline.Among the E compounds,the higher activity was the compound w-4-14(IC₅₀=8.20?M)introduced with 4-OCH₃benzylamine and the compound w-4-18(IC₅₀=29.51?M)introduced with 4-CH₃benzylamine.The LCA derivative anti-inflammatory activity experiment provides the basis for designing more derivatives with anti-inflammatory activity in the future.