Structure-activity Relationship of α,β-Unsaturated Ketones for the Suppression of Tumor Necrosis Factor-α and Nitric Oxide Production in Lipopolysaccharide-stimulated Macrophages and Their Molecular Orbital Energies

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Chalcones and the related α,β-unsaturated ketones were studied to discover their inhibitory activities for tumor necrosis factor-α (TNF-α) and nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264 macrophages and their molecular orbital energies. The simple α,β-enone, 1-penten-3-one (6), showed the activities stronger than or comparable to those of the phenyl-conjugated α,β-enones including natural chalcones, suggesting that the α,β-enone structure in 6 is enough to induce the above inhibition. The correlation between the inhibitory activities and the frontier molecular orbital energies suggests that (1) the enones primarily act as Michael acceptors in the inhibition with high susceptibility to the steric hindrance from their molecular structures, and (2) a possibility remains that the phenyl-conjugated enones and those with phenolic hydroxy groups act as electron-donating agents in the inflammatory process. Thus, the α,β-enone core singly suppresses the TNF-α and NO production in LPS-stimulated macrophages, but the conjugated hydroxyphenyl rings in chalcones are also important for their pharmacological activity.