New Sinomenine Pyrazine Derivatives Having Two Unequal Vicinal Substituents And Their Inhibitory Activity Against TNF-α Production

Sinomenine, an alkaloid extracted from the Chinese medicinal plant Sinomenium acutum, exhibiting a variety of pharmacological activities including anti-inflammatory, immunosuppressive, analgesic, antihypertensive and antiarrhythmic effects. Sinomenium acutum has been used in the treatment of rheumatoid arthritis in China and other Asian countries for many centuries. Sinomenine, as an important ingredient of Sinomenium acutum, also has been applied with other drug materials in medical treatments. While, pure sinomenine only exhibits weak biological activity, and the large does often causes uncertain side effects, and the mechanisms of action associated with its treatment effects are still ambiguous yet. To improve its druggability bioactivities, a considerable number of modifications of sinomenine have been reported in the past several decades.Several new types of sinomenine derivatives have been studied in our group by Drs. Zhou and Lou, including the modifications of C-1 site in A ring, C-4 site in B ring and embedment of C ring with pyrazine ring as well. Among these, derivative 1020 exhibits the highest inhibitory rate of TNF-a production up to 66% IR at 10μM. Further modifications also have been made by M. Wang of our group. He developed a series of sinomenine derivatives, which embedded with a pyrazine ring having two equal vicinal substituents. However, a further effort failed to prepare the pure pyrazine derivatives with unequal substituents.In this work, we reported our successful synthesis of 24 sinomenine-pyrazine derivatives having two different vicinal substituents via Suzuki couplings. The TNF-α inhibitory assay showed that most of these new derivatives exhibited higher inhibition rate than sinomenine, and several compounds were even higher than that of SB202190. In meanwhile, we studied the synthesis of molecular probes for future mechanism study. Unfortunately, the TNF-α inhibitory rate of two synthesized molecular probes are not very satisfactory. Further work is still in progress.