Synthesis and biochemical characterization of a series of 17alpha-perfluoroalkylated estradiols as selective ligands for estrogen receptor alpha.

Article Details

Citation
Copy to clipboard

Eignerova B, Sedlak D, Dracinsky M, Bartunek P, Kotora M

Synthesis and biochemical characterization of a series of 17alpha-perfluoroalkylated estradiols as selective ligands for estrogen receptor alpha.

J Med Chem. 2010 Oct 14;53(19):6947-53. doi: 10.1021/jm100563h.

PubMed ID
20812681 [ View in PubMed
]
Abstract

Despite intensive research efforts, the distinct biological roles of two closely related estrogen receptors, ERalpha and ERbeta, are only partially understood. Therefore, ligands selective for either of two isotypes are useful research tools because they allow for exerting a desired subset of biological effects mediated by only one of the receptors. Here we report on the synthesis of a new class of potent and selective ligands for ERalpha represented by a series of 17alpha-substituted estradiols bearing lipophilic perfluoroalkyl chains. These 17alpha-perfluoroalkylated estradiols were synthesized by Ru-catalyzed cross metathesis reactions of 17alpha-allyl- or 17alpha-vinylestradiols with perfluoroalkylpropenes. Compounds were tested in both agonistic and antagonistic modes using a panel of stable steroid receptor reporter cell lines established in U2OS cells and consisting of ERalpha-LBD, ERbeta-LBD, GR-LBD, and MR-LBD reporters. Some of the compounds are potent and selective agonists of ERalpha, exhibiting weak partial to no detectable agonistic activity on ERbeta. Notably, 11c is the most ERalpha selective ligand of the prepared compounds because it activates ERalpha but inhibits ERbeta. In addition, some compounds are pure agonists on ERalpha but show mixed agonistic/antagonistic profile on ERbeta which is a typical pattern observed for selective estrogen receptor modulators (SERMs).

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
AldosteroneMineralocorticoid receptorEC 50 (nM)0.338N/AN/ADetails
AldosteroneMineralocorticoid receptorIC 50 (nM)9.27N/AN/ADetails
DexamethasoneGlucocorticoid receptorIC 50 (nM)0.508N/AN/ADetails
EstradiolEstrogen receptor alphaEC 50 (nM)2.77N/AN/ADetails
EstradiolEstrogen receptor alphaIC 50 (nM)21.04N/AN/ADetails
EstradiolEstrogen receptor betaEC 50 (nM)0.458N/AN/ADetails
EstradiolEstrogen receptor betaIC 50 (nM)10.74N/AN/ADetails