A chromone analog inhibits TNF-α induced expression of cell adhesion molecules on human endothelial cells via blocking NF-κB activation Original Research Article

The interaction between leukocytes and the vascular endothelial cells (EC) via cellular adhesion molecules plays an important role in various inflammatory and immune diseases. The molecules that block these interactions have been targeted as potential therapeutic targets for acute and chronic inflammatory diseases. In an effort to develop potent cell adhesion molecule inhibitors, a series of chromone derivatives bearing alkoxycarbonylvinyl unit at the C-3 position, that is, the chromones 8a–d and 9a–d, were designed and synthesized, and evaluated for their ICAM-1 inhibitory activity on human endothelial cells as well as their effect on NADPH-catalyzed rat microsomal lipid peroxidation. A structure–activity relationship was established and we found that length of the alkyl moiety of the chromone-3-yl-acrylate is important for this activity. Further, we found that incorporation of unsaturation in the alcohol moiety increases the potential of the compound for the inhibition of TNF-α induced expression of ICAM-1 and also for the inhibition of lipid peroxidation. Out of the screened compounds, the most potent compound ethyl trans-3-(4-oxo-4H-1-benzopyran-3-yl)-acrylate (8a) was taken for further study. We have found that compound 8a also significantly inhibited the TNF-α induced expression of VCAM-1 and E-selectin, which play key roles in various inflammatory diseases. This inhibition was found to be concentration dependent. The functional consequences of inhibiting cell adhesion molecules were studied by performing cell-adhesion assay. We found that compound 8a significantly blocks the adhesion of neutrophils to endothelial monolayer. To elucidate the molecular mechanism of inhibition of cell adhesion molecules, we investigated the status of nuclear transcription factor-κB (NF-κB) and were able to establish that compound 8a significantly blocked the TNF-α induced activation of NF-κB.