Synthesis and Biochemical Characterization of a Series of 17α-Perfluoroalkylated Estradiols as Selective Ligands for Estrogen Receptor α

Despite intensive research efforts, the distinct biological roles of two closely related estrogen receptors. FRG. and ER/beta, 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 ER alpha represented by a series of 17 alpha-substituted estradiols bearing lipophilic perfluoroalkyl chains. These 17 alpha-perfluoroalkylated estradiols were synthesized by Ru-catalyzed cross metathesis reactions 17 alpha-allyl- or 17 alpha-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 ER alpha-LBD, ER/beta-LBD, GRLBD, and MR-LBD reporters. Some of the compounds are potent and selective agonists of ER alpha, exhibiting weak partial to no detectable agonistic activity on ER/beta. Notably, He is the most ER alpha selective ligand of the prepared compounds because it activates ER alpha, but inhibits ER/beta. In addition, some compounds are pure agonists on ER alpha, but show mixed agonistic/antagonistic profile on ER/beta which is a typical pattern observed for selective estrogen receptor modulators (SERMs).