Synthesis of Novel Estrogen Receptor Antagonists Using Metal-Catalyzed Coupling Reactions and Characterization of Their Biological Activity

Estrogen receptor (ER) antagonists are valuable in the treatment of ER-positive human breast cancer. In this study, we designed and synthesized nine new derivatives of 17 beta-estradiol (E-2) with a bulky side chain attached to its C-7 alpha position, and determined their ER antagonistic activity using in vitro bioassays. Four of the derivatives showed a strong inhibition of ER alpha transactivation activity in a luciferase reporter assay and blocked ER alpha interactions with coactivators. Similarly, these derivatives also strongly inhibited the growth of the ER alpha-positive human breast cancer cells. Computational docking analysis was conducted to model the interaction of these antagonists with the human ER alpha and showed that they could tightly bind to the ER alpha in a manner similar to that of ICI-182,780, a pure ER antagonist. These results provide an example that attachment of a bulky side chain to the C-7 alpha position of E-2 can produce ER antagonists with ER affinity comparable to that of ICI-182, 780.