Estrogenic and antiestrogenic activities of 2,4-diphenylfuran-based ligands of estrogen receptors alpha and beta.

The estrogen receptor (ER) exists in two isoforms ERalpha and ERbeta with a different distribution in the body and different functions which are not clearly identified yet. Thus, it is desirable to have both agonists and antagonists with selectivity for one or the other ER isoform available. In a previous study we showed that 2,5-diphenylfurans can be converted into pure antiestrogens with preference for ERalpha. When the arrangement of the phenyl rings was altered to a 2,4-substitution, the alpha-selectivity was lost as demonstrated by comparative assays using recombinant human ERalpha and ERbeta. 3,5-Dialkyl-2,4-bis(4-hydroxyphenylfurans) were shown to act as agonists with preference for ERbeta. Replacement of one of the alkyl groups by the [(pentylsulfanyl)propyl]aminohexyl side chain afforded estrogen antagonists without receptor selectivity. These derivatives were characterized as pure antiestrogens in transcription and proliferation assays in ER+ MCF-7 breast cancer cells. The most potent antagonists displayed IC50 values of ca. 20 nM (fulvestrant 4 nM). The data showed that the 2,4-arrangement of the phenyl rings in the furan structure increases the binding affinity for ERbeta in comparison to the isomeric 2,5-diphenylfurans but does not lead to a pure antagonist with selectivity for ERbeta.