Synthesis of novel estrogen receptor antagonists using metal-catalyzed coupling reactions and characterization of their biological activity.

ABSTRACT: 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?-estradiol (E2) with a bulky side chain attached to its C-7? position, and determined their ER antagonistic activity using in vitro bioassays. Four of the derivatives showed a strong inhibition of ER? transactivation activity in a luciferase reporter assay and blocked ER? interactions with coactivators. Similarly, these derivatives also strongly inhibited the growth of the ER?-positive human breast cancer cells. Computational docking analysis was conducted to model the interaction of these antagonists with the human ER? and showed that they could tightly bind to the ER? 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? position of E2 can produce ER antagonists with ER affinity comparable to that of ICI-182,780.

SUBMITTER: Jiang XR 

PROVIDER: S-EPMC3666588 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature