Discovery of novel oestrogen receptor α agonists and antagonists by screening a revisited privileged structure moiety for nuclear receptors

Abstract

Bisphenol A (BPA) is used as an industrial raw material for polycarbonate plastics and epoxy resins; however, various concerns have been reported regarding its status as an endocrine-disrupting chemical. BPA interacts not only with oestrogen receptors (ERs) but constitutive androstane receptor, pregnane X receptor, and oestrogen-related receptor γ (ERRγ); therefore, the bisphenol structure represents a privileged structure for the nuclear-receptor superfamily. Here, we screen 127 BPA-related compounds by competitive-binding assay using [ 3 H]oestradiol and find that 20 compounds bind to ERα with high affinity. We confirm most of these as ERα agonists; however, four compounds, including bisphenol M and bisphenol P act as novel antagonists. These structures harbour three benzene rings in tandem with terminal hydroxy groups at para -positions, with this tandem tri-ring bisphenol structure representing a novel privileged structure for an ERα antagonist. Additionally, we perform an ab initio calculation and develop a new clipping method for halogen bonding or non-covalent interaction using DV-Xα evaluation for biomolecules.

Bisphenol A derivatives act as novel coactivator binding inhibitors for estrogen receptor β

“…2E). BPC showed the strongest antagonistic activity, with additional halogen-containing bisphenols (i.e., HPTE, and BPAF) also elicited antagonistic activities, consistent with previous reports (31)(32)(33) 15) functioned as a weak antagonist, demonstrating that fluorene derivatives 14 and 15 can exhibit both ERb and ERa antagonistic activity (34,35). With the exception of the tricyclic bisphenols, these findings indicate that most bisphenol derivatives with strong ERb binding functioned as antagonists, even though they showed only agonist activities to ERa (34).…”

“…(20) showed no agonist activity against ERb. These findings contrast with ERa, where the majority of bisphenol derivatives with strong binding affinity also showed strong agonistic activity (34).…”

“…We previously reported that tricyclic bisphenols, i.e., Bisphenol M, α, α, α′-tris(4hydroxyphenyl)-1-ethyl-4-isopropylbenzene, bisphenol P, and α,α′-Bis(4-hydroxy-3,5dimethylphenyl)-1,4-diisopropylbenzene, act as antagonists against ERa because of the steric hindrance caused by the third aromatic ring structure (34). This study showed that this feature is also valid for ERb; tricyclic bisphenols act as antagonists not only for ERa but also ERb.…”

Bisphenols and Leydig Cell Development and Function

“… a Potency of bisphenols in estrogen receptor (ESR) and androgen receptor (NR3C4) luciferase reporter gene assays ( 154 ); b Ligand binding assay ( 155 ); c Ligand binding assay ( 156 ); IA, inactive; ND, not detected; -, no active activity; REL, potency relative to BPA . …”

“…A series of estrogen receptor luciferase assays of BPA analogs in all 127 test compounds showed that BPC bound ESR1 with the highest affinity, with IC 50 of 2.81 nM, and other BPA analogs such as BPAF (53.4 nM), BPM (56.8 nM), BPZ (56.9 nM), BPP (176 nM), BPB (195 nM), BPAP (259 nM), and BPA (1,780 nM) ( 155 ) ( Table 3 ). Estrogen receptor binding experiments have shown similar effects of these BPA analogs ( 154 , 156 ) ( Table 3 ).…”