Effects of Geranyloxycinnamic Acids on COX-2 and iNOS Functionalities in LPS-Stimulated U937 Mononuclear Cells

A series of naturally occurring and semisynthetic O-geranyl cinnamic acids and their conjugates with the iNOS inhibitor N-omega-nitro-L-arginine methyl ester have been synthesized and evaluated for their effects on expressions of COX-2 and iNOS, antioxidant activity, and PGE2 and NO production in LPSstimulated U937 mononuclear cells. All adducts showed little or no effect on iNOS functionality in terms of NO release. A much more significant activity has been recorded on PGE2 biosynthesis for which the sample substituted with a -NO2 group in position 3 of the aromatic ring revealed an effect in the nM range both for the L-NAME conjugated product and the parent compound (IC50= 0.71 mu M and 0.1 mu M respectively). Preliminary docking studies have been carried out to clarify the mechanism of COX-2 inhibition, and they suggest that the geranyloxy side chain is likely to play an important role for the observed activity and that structural modifications are able to tune such effects.