A series of new resveratrol analogues were designed and synthesized and their inhibitory activities against aromatase were evaluated. The crystal structure of human aromatase (PDB 3eqm) was used to rationalize the mechanism of action of the aromatase inhibitor 32 (IC 50 0.59 µM) through docking, molecular mechanics energy minimization, and computer graphics molecular modeling, and the information was utilized to design several very potent inhibitors, including compounds 82 (IC 50 70 nM) and 84 (IC 50 36 nM). The aromatase inhibitory activities of these compounds are much more potent than that for the lead compound resveratrol, which has an IC 50 of 80 µM. In addition to aromatase inhibitory activity, compounds 32 and 44 also displayed potent QR2 inhibitory activity (IC 50 1.7 µM and 0.27 µM, respectively) and the high-resolution X-ray structures of QR2 in complex with these two compounds provide insight into their mechanism of QR2 inhibition. The aromatase and quinone reductase inhibitors resulting from these studies have potential value in the treatment and prevention of cancer.
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.
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