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

摘要

A series of naturally occurring and semisynthetic O-geranyl cinnamic acids and their conjugates with the iNOS inhibitor N_ω- nitro-L-arginine methyl ester have been synthesized and evaluated for their effects on expressions of COX-2 and iNOS, antioxidant activity, and PGE_2 and NO production in LPS- stimulated 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 PGE_2 biosyn- thesis for which the sample substituted with a -NO_2 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 (IC_(50) =0.71 mM and 0.1 μM 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.