Structure–Activity Relationship of Resveratrol and Its Analogue 4,4'-Dihydroxy-Trans-Stilbene Toward the Endothelin Axis in Human Endothelial Cells

Resveratrol inhibits endothelin-1, a vascular tension regulator. We synthesized the resveratrol analogue
4,4’dihydroxy-trans-stilbene with 2 hydroxyl groups in the 4 and 4’ position to obtain a molecule more active than resveratrol
(3,4’,5-trihydroxy-trans-stilbene). The results demonstrate that 4,4’-dihydroxy-trans-stilbene led to a significant decrease in
total endothelin-1 secretion and in endothelin-1 messenger RNA (mRNA) levels in human endothelial cells. In addition,
resveratrol and its analogue decreased endothelin-converting enzyme-1 mRNA levels and further reduced the activity of the
enzyme. 4,4’-dihydroxy-trans-stilbene was more active than resveratrol because the new molecule exerted greater activity at
the level of endothelin synthesis and conversion, even at a lower concentration. Although 4,4’-dihydroxy-trans-stilbene and
resveratrol inhibited formation of reactive oxygen species and lipid peroxidation, the treatment of cells with different oxidant
agents did not modify the endothelin-1 release. This finding suggests that the inhibition of endothelin-1 secretion is independent
of the antioxidant properties of the 2 compounds. On the basis of these results, the resveratrol analogue 4,4’-
dihydroxy-trans-stilbene could be a promising chemopreventive agent against cardiovascular disease.