Ligands which selectively activate only one of the estrogen receptors, ERα or ERβ, are current pharmaceutical targets. Previously, we have reported on substituted cis A-CD ligands in which the B-ring of the steroidal structure has been removed and cis refers the stereochemistry of the CD ring junction as compared to trans in estradiol. These compounds often showed good potency and selectivity for ERβ. Here we report the synthesis and binding affinities for a similar series of trans A-CD ligands, and compare them to the cis-series. Counterintuitively, trans A-CD ligands, which are structurally more closely related to the natural ligand estradiol, show weaker binding and less β-selectivity than their cis-counterparts.

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Keywords ERα, ERβ, Estrogen receptor, Ligand synthesis, β-Selectivity
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Journal Bioorganic and Medicinal Chemistry Letters
Dabrota, C. (Cristian), Asim, M. (Muhammad), Choueiri, C. (Christine), Gargaun, A. (Ana), Korobkov, I. (Ilia), Butt, A. (Ammara), … Durst, T. (Tony). (2014). Synthesis and receptor binding in trans-CD ring-fused A-CD estrogens: Comparison with the cis-fused isomers. Bioorganic and Medicinal Chemistry Letters, 24(16), 3841–3844. doi:10.1016/j.bmcl.2014.06.066