De Novo Design, Synthesis, and Evaluation of Novel Nonsteroidal Phenanthrene Ligands for the Estrogen Receptor

Abstract

Although there are many estrogen receptor antagonists with improved tissue selectivity profiles compared with tamoxifen, optimal tissue selectivity has not yet been demonstrated. As such there is still a need for additional diversity and new chemical scaffolds to allow for exploration of improved tissue selectivity. Here, we describe the discovery of a novel phenanthrene scaffold for estrogen receptor ligands utilizing a ligand based de novo design approach. The nanomolar binding of phenanthrenes, 12b,c, 14b,c, and 15 against human recombinant ER(alpha) indicates that our ligand based de novo design approach was successful. From a gene transfection assay, 12b,c, 14b,c, and 15 displayed only antagonistic activity with no observable agonistic activity. The alkyl 9,10-dihydrophenanthrene 16 (presumably a racemic mixture) was a substantially more potent ER binder than the phenanthrenes. It also displayed only antagonistic activity and was effective at inhibiting estradiol stimulated MCF-7 cell proliferation. These results demonstrate that this phenanthrene (and 9,10-dihydrophenanthrene) scaffold warrants further study as potential selective estrogen receptor modulators and/or pure antiestrogens.

Tamoxifen augments the innate immune function of neutrophils through modulation of intracellular ceramide

“…Because tamoxifen is generally described to have antagonist activity at the estrogen nuclear receptors ERα and ERβ and agonist activity at the G protein-coupled estrogen receptor GPR30, we attempted to replicate these results using selective agonists/antagonists. In these studies, NET production was not observed in response to treatment with MPP or PHTPP (selective ERα and ERβ antagonists, respectively 12 , 13 ), G-1 (a GPR30 agonist 14 ) or fulvestrant (a SERM that mimics the mixed agonist/antagonist characteristics of tamoxifen 15 , 16 ) ( Supplementary Fig. 3 ), indicating that tamoxifen-induced NET production is mediated by an estrogen receptor-independent mechanism.…”

Non-Steroidal Subtype Selective Estrogens

“…SignalGene explored the use of phenantrenes as SERMtype ligands for the estrogen receptors [68]. All of the phenantrenes prepared showed very low affinity for either ER.…”

Novel biosensors for the detection of estrogen receptor ligands

“…These ER ligands are then tested in vivo to determine whether they act as SERMS in particular tissues [4][5][6][7][8][9]. Traditionally, ER ligands have been identified using estrogen competition assays, which use radio-or fluorescently labeled estrogen [5,[10][11][12][13][14][15][16].…”