Background: High mobility group box 1 (HMGB1)-receptor for advanced glycation endo-products (RAGE) axis serves as a key player in linking
inflammation and
carcinogenesis. Recently,
papaverine was revealed to suppress the HMGB1-RAGE inflammatory signaling pathway and
cancer cell proliferation. Therefore, a dual suppressor targeting this axis is expected to become a new type of therapeutic agent to treat
cancer. Methods:
Papaverine 3D pharmacophore mimetic compounds were selected by the LigandScout software from our in-house, anti-
cancer chemical library and assessed for their anti-inflammatory activities by a HMGB1-RAGE-mediated
interleukin-6 production assay using macrophage-like RAW264.7 cells. Molecular-biological analyses, such as Western blotting, were performed to clarify the mechanism of action. Results: A unique 6-methoxy-3-hydroxy-styrylchromone was found to possess potent anti-inflammatory and anti-
cancer activities via the suppression of the HMGB1-RAGE-extracellular signal-regulated
kinase 1/2 signaling pathway. Furthermore, the 3D pharmacophore-activity relationship analyses revealed that the
hydroxyl group at the C4' position of the
benzene ring in a 3-styryl moiety was significant in its dual suppressive effects. Conclusions: These findings indicated that this compound may provide a valuable scaffold for the development of a new type of anti-
cancer drug possessing anti-inflammatory activity and as a tool for understanding the link between
inflammation and
carcinogenesis.