Resveratrol, a naturally occurring stilbene found in the human diet, has been shown to mediate a host of biological activities. It has been reported to display both estrogenic and anti‐estrogenic activities, depending on cell type and conditions, but inhibition of aromatase activity is weak (IC50 = 25 µM). We have conducted a systematic study in which about 60 substituted stilbenes were synthesized and evaluated for biologic potential. Several of these synthetic derivatives were found to inhibit aromatase activity with IC50 values in the sub‐micromolar range. Within the series, structure‐activity relationships demonstrated substitution of an amine group produced greater inhibition than a nitro group, and the position of these groups was of greater importance than the number and position of methoxy groups. Compound 1 [(E)‐4‐(3,5‐dimethoxystyryl)aniline] was one of the most potent inhibitors, with an IC50 of 0.31 µM, which is comparable to that of aminoglutethimide (IC50 = 0.2 µM). In addition, crystallographic analysis revealed compound 1 binds to quinone reductase 2 in an orientation similar to that of resveratrol, but demonstrates greater inhibitory potency. Compound 1 has been synthesized on a multigram scale, oral administration with laboratory animals indicates excellent absorption and good metabolic stability, and more advanced testing is underway. (Supported by program project P01 CA48112 awarded by the National Cancer Institute)
Citation Information: Cancer Prev Res 2010;3(1 Suppl):A68.