Synthesis and biological evaluation of a novel series of furans: Ligands selective for estrogen receptor alpha

A variety of nonsteroidal systems can function as ligands for the estrogen receptor (ER), in some cases showing selectivity for one of the two ER subt ypes, ER alpha or ER beta We have prepared a series of heterocycle-based (f urans, thiophenes, and pyrroles) ligands for the estrogen receptor and asse ssed their behavior as ER ligands. An aldehyde enone conjugate addition app roach and an enolate alkylation approach were developed to prepare the 1,4- dione systems that were precursors to the trisubstituted and tetrasubstitut ed systems, respectively. All of the diones were easily converted into the corresponding furans, but formation of the thiophenes and pyrroles from the more highly substituted 1,4-diones was problematical. Of the systems inves tigated, the tetrasubstituted furans proved to be most interesting. They we re ER alpha binding-and potency-selective agents, with the triphenolic 3-al kyl-2,4,5-tris(4-hydroxyphenyl)furans (15a-d) displaying generally higher s ubtype binding selectivity than the bisphenolic analogues (15f-i). Binding selectivity for ER alpha was as high as 50-70-fold, and transcriptional act ivation studies showed that several members of this series were ER alpha se lective agonists, with the best compound [3-ethyl-2,4,5-tris(4-hydroxypheny l)furan, 15b] having full transcriptional activity on ER alpha while being inactive on ER beta. Comparative binding affinity analysis and molecular mo deling were used to investigate the preferred binding mode adopted by the f uran ligands, which appears to have the C(2) phenol mimicking the important role of the A-ring of estradiol. These ligands should be useful in studyin g the biological roles of both ER alpha and ER beta and they might form the basis for the development of novel estrogen pharmaceuticals.