Synthesis and biological evaluation of novel sinomenine derivatives as anti-inflammatory agents

Sinomenine (1) is clinically available for the treatment of rheumatoid arthritis (RA), however, its efficacy is quite weak. In the present study, a library of novel sinomenine-based homodimers and monomers through variable-length linkers were designed and synthesized, and their bioactivities were evaluated using RAW264.7 cells and mice. Among the compounds, 2f and 3b possessed much more potent inhibitory effects on the production of nitric oxide (NO), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) than 1. Preliminary mechanism investigation revealed that 3b inhibited nuclear factor-κB (NF-κB) signaling pathway specifically, 2f suppressed both NF-κB and mitogen-activated protein kinase (MAPK) cascades. Moreover, 3b and 2f significantly alleviated the lipopolysaccharide (LPS)-induced mortality. These two compounds might serve as valuable candidates for anti-inflammatory drug discovery.

Novel sinomenine-based homodimers and monomers were synthesized and their anti-inflammatory effects and preliminary mechanism were investigated using RAW264.7 cells and mice. Figure optionsDownload as PowerPoint slideHighlights
► A library of novel sinomenine-based homodimers and monomers was synthesized.
► 2f and 3b significantly inhibited productions of NO, IL-6 and TNF-α.
► 3b inhibited NF-κB pathway specifically and 2f suppressed NF-κB and MAPK cascades.
► 3b and 2f exhibited anti-inflammatory effects in mice.