Synthesis and Biological Evaluation of a Novel Series of Furans:  Ligands Selective for Estrogen Receptor α

Abstract

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 subtypes, ER alpha or ER beta. We have prepared a series of heterocycle-based (furans, thiophenes, and pyrroles) ligands for the estrogen receptor and assessed their behavior as ER ligands. An aldehyde enone conjugate addition approach and an enolate alkylation approach were developed to prepare the 1,4-dione systems that were precursors to the trisubstituted and tetrasubstituted 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 investigated, the tetrasubstituted furans proved to be most interesting. They were ER alpha binding- and potency-selective agents, with the triphenolic 3-alkyl-2,4,5-tris(4-hydroxyphenyl)furans (15a-d) displaying generally higher subtype binding selectivity than the bisphenolic analogues (15f-i). Binding selectivity for ER alpha was as high as 50-70-fold, and transcriptional activation studies showed that several members of this series were ER alpha selective agonists, with the best compound [3-ethyl-2,4,5-tris(4-hydroxyphenyl)furan, 15b] having full transcriptional activity on ER alpha while being inactive on ER beta. Comparative binding affinity analysis and molecular modeling were used to investigate the preferred binding mode adopted by the furan 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 studying the biological roles of both ER alpha and ER beta, and they might form the basis for the development of novel estrogen pharmaceuticals.

Synthesis and biodistribution of fluorine-18-labeled fluorocyclofenils for imaging the estrogen receptor

“…The discovery that there are two ER subtypes, ERα and ERβ, having different tissue distributions, different biological roles, and different activity levels [19,20], has further stimulated the search for ER ligands that might act selectively on these subtypes [20], and has led to the development of the ERα-selective pyrazole PPT [21], as well as other furan, and pyrrole derivatives [22], and the ERβ-selective diarylpropionitrile DPN [23], as well as other cyclofenil, and tetrahydrochrysene derivatives ( Figure 1) [24,25]. Also of interest is the development of ER ligands that might be effective in imaging the ERs in a subtype-selective manner [26,27].…”

Oestrogen receptor knockout mice: roles for oestrogen receptors alpha and beta in reproductive tissues

“…However, ER␣ and ER␤ both bind oestradiol and interact with ERE sequences. Compounds with preferential binding for either ER␣ or ER␤ have also been synthesized, illustrating that the binding activities of ERs can be distinguished (Katzenellenbogen and Katzenellenbogen, 2000;Meyers et al, 2001;Mortensen et al, 2001;Shiau et al, 2002). Both receptors are also distinct in their transcriptional activities, with ER␤ showing less potent activity than ER␣ in most contexts as well as the ability to inhibit ER␣ activity (Kuiper and Gustafsson, 1997;Paech et al, 1997;Barkhem et al, 1998;Kuiper et al, 1998;Montano et al, 1998;Hall and McDonnell, 1999).…”

Breast Cancer, Estrogen Receptor and Ligands

“…17) were found in biological studies to possess a very interesting character [113]. Furan 1 proved to be an agonist with high selectivity for ERa versus ERb in both ER-binding affinity and transcriptionalactivation activity in human endometrial cancer HEC-1 cells.…”

“…This selectivity benefits allegedly by the third phenolic hydroxyl on the C(5) phenyl group, which is possibly H-bonded to the amino acid Thr347 within the ERa LBD according to the molecular modeling investigation on the binding orientation of a furan ligand in ERa. Furan 2, derived by grafting an N-piperidinylethyl side chain on the C(4) phenol of furan 1, was an ERa-selective antagonist with high binding affinity [114].…”