Regio-controlled synthesis of unsymmetrical pyrazine-fused sinomenine derivatives and discriminate substitution effects on TNF-α inhibitory activity

A unified regio-controlled synthetic protocol combined with the use of Suzuki couplings, in a diverse fashion, has been developed and successfully applied to the synthesis of various pairs of unsymmetrical pyrazine-fused derivatives of sinomenine, a natural immunemodulating alkaloid. Introduction of two vicinal aromatic substituents to the pyrazine functionality resulted in significant improvement of TNF-α inhibitory activity, and a number of new derivatives exhibited even higher inhibition rate than that of positive control SB202190. In addition, discriminate but complicated substitution effects of these sinomenine–pyrazine hybrids have been observed on tumor necrosis factor-α (TNF-α) inhibitory activity.

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