| Rheumatic Arthritis（RA）is a chronic and aggressive autoimmune disease characterized by cytokine-mediated inflammation of the synovial membrane and damage to the body’s cartilage and bones,especially to the feet of the opponent.In severe cases,people will lack the labor force and evenare life-threatening.RA is mostly occurred in middle-aged and elderly people.However,depending on the physical fitness of each person,the speed of disease development tends to be different.Some patients with RA develop rapidly characterized as joint deterioration and dysfunction,which ultimately leads to unfavorable results.According to epidemiological reports,the prevalence of RA in the general population is between 1%and 6%,and the incidence can reach 23.1%in special populations（such as those working in cool,wet or underground mines）.RA can occur in all ages,with higher frequencyamong the ages ranging from35 to 50,and the incidence of women is three times that of men.Sinomenine is an alkaloid derived from the genus Asteraceae,which is structurally isoquinoline and has various biological activities.It is mainly used for the treatment of rheumatic and rheumatoid arthritis and anti-arrhythmia.However,sinomenine has shortcomings such as low activity,instability to light and heat,rapid metabolism in the body,and partial allergic reactions,so its clinical application is relatively rare.In order to make the traditional anti-rheumatic arthritis drug sinomenine more widely popular,this paper combines the previous research basis and synthesize a series of sinomenine derivatives.The in vitro anti-inflammatory activity of the compounds was studied in order to obtain a class of highly effective and low-toxic sinomenine derivatives.In this paper,sinomenine hydrochloride was used as a lead compound to introduce a bromine atom at the 1-position by a bromine radical substitution reaction,and then an aryl group（including a phenyl group）was introduced at the 1-position of the A ring of sinomenine by a palladium-catalyzed SuZuki coupling reaction.A total of 29sinomenine derivatives were synthesized,of which 24 compounds were introduced into various alkyl-substituted aromatic rings,4 compounds were introduced into naphthalene ring,phenanthrene ring,anthracene ring,and 1 compound was introduced into pyridine.ring.All compounds were new compounds and the structures were confirmed by 1H NMR,13C NMR and MS.This study used reporter gene method to study the effect of sinomenine derivatives on NF-κB transcriptional activity.In vitro activity experiments showed that 21 of the 29new compounds were more active than the lead compound sinomenine,and 4h,4p,4s,4v with significantly better activity could be further studied as candidate drugs for the development of rheumatoid arthritis.Further studies on structure-activity relationship showed that the anti-inflammatory activity of sinomenine was observed when the phenyl group was introduced into the phenyl group to have a good anti-rheumatic arthritis activity,and various groups were introduced on the benzene ring.Different degrees of change,it is speculated that the introduction of different substituents on the benzene ring can affect its anti-rheumatic arthritis activity,and the biological activity of the electron-withdrawing group and the electron-donating group are significantly changed when the benzene ring is introduced.Here,the structure-activity relationship is more complicated and needs further discussion.When introducing various groups of substituted phenyl groups,we found that the introduction of substituents at the meta position of the benzene ring is more biologically active than the para and ortho positions.When an aromatic heterocycle is introduced,the biological activity of the pyridine ring against rheumatoid arthritis is greater than that of the benzene ring,which we speculate may be related to the nitrogen atom in the pyridine ring.In the expansion of the substrate,it was found that the rheumatoid arthritis activity of the large groups such as naphthalene ring,phenanthrene ring and anthracene ring is significantly lower than that of the benzene ring,which is supposed to be the effect of steric hindrance.Hnece the introduction of a large group will result inthe decreasing anti-RA activity. |
