Bisphenol A derivatives as potent inhibitors of 11β-hydroxysteroid dehydrogenase 2: A structure-activity study

Bisphenol A (BPA) has been restricted for its use due to endocrine-disrupting effects and its benzene-ring-substituted derivatives (BPADs) are increasingly used. However, their effects on 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), a pivotal enzyme in glucocorticoid regulation, remain poorly characterized. Here, we evaluated, for the first time, how BPADs modulate 11β-HSD2 inhibition, providing mechanistic insights into their endocrine-disrupting potential. This study evaluated six BPADs, identifying 4-hydroxyphenyl-naphthalene (BPH) as the most potent inhibitor (human IC₅₀ = 1.26 µM; rat IC₅₀ = 4.17 µM), with structure-activity relationships (SAR) revealing critical roles for hydrophobicity (LogP) and steric bulk. Enzyme kinetic inhibition analyses demonstrated competitive or mixed-type inhibition of BPADs, and surface plasmon resonance (SPR) confirmed direct binding of BPH to 11β-HSD2. Molecular docking further highlighted key interactions with residues (Asn167, Lys236) in the steroid-binding pocket. Cellular assays in BeWo cells confirmed functional inhibition of endogenous 11β-HSD2. Notably, human 11β-HSD2 exhibited greater sensitivity than rat ortholog towards BPADs, attributed to a Ser92→Thr92 substitution of 11β-HSD2 sequences. These findings positioned BPADs as novel chemical probes for 11β-HSD2 studies and warranted investigation into their endocrine-disrupting potential, particularly in prenatal contexts where placental 11β-HSD2 safeguards fetal development.