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. 2023 Sep 12;13(39):27359-27362.
doi: 10.1039/d3ra04656g. eCollection 2023 Sep 8.

Development of subtype-selective estrogen receptor modulators using the bis(4-hydroxyphenyl)silanol core as a stable isostere of bis(4-hydroxyphenyl)methanol

Yuichiro Matsumoto  1 , Yuichi Hashimoto  1 , Shinya Fujii  2
Affiliations

Development of subtype-selective estrogen receptor modulators using the bis(4-hydroxyphenyl)silanol core as a stable isostere of bis(4-hydroxyphenyl)methanol

Yuichiro Matsumoto et al. RSC Adv. .

Abstract

In this study, we synthesized and evaluated silanol-based bisphenol derivatives as stable isosteres of bis(4-hydroxyphenyl)methanol. The developed silanols exhibited estrogen receptor (ER)-modulating activity. Among them, bis(4-hydroxyphenyl)(methyl)silanol (5a) showed a characteristic ER subtype selectivity, namely, antagonistic activity toward ERα and agonistic activity toward ERβ. Docking simulation indicated that the silanol moiety plays a key role in this selectivity. Our results suggest that silanol-based bisphenols offer a unique scaffold for biologically active compounds.

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Conflict of interest statement

There are no conflicts to declare.

Figures

Fig. 1
Fig. 1. (A) Structures of some silanol-based biologically active compounds. (B) Structures and properties of bis(4-hydroxyphenyl)methanols (3) and bis(4-hydroxyphenyl)silanols (5). Compounds 3 are easily converted to quinone methides 4, whereas silanols 5 cannot generate the corresponding quinone congeners.
Scheme 1
Scheme 1. Synthesis of the designed bis(4-hydroxyphenyl)silanols 5a–5h.
Fig. 2
Fig. 2. Dose–response relationship of 5a in reporter gene assay using HEK293 cells. Compound 5a induced transcription of ERβ, but suppressed the transcription of ERα induced by E2. Data are presented as mean ± SD. TAM: tamoxifen.
Fig. 3
Fig. 3. Docking models of silanol 5a and 5f with hERα LBD (PDB ID: 3ERT) obtained with AutoDock 4.2. The protein surface is indicated as a grey mesh. (Left) Docking model of 5a (yellow) in the hERα LBD. (Center) Docking model of 5f (cyan) in the hERα LBD. (Right) Superimposition of the docking models of 5a and 5f.
Fig. 4
Fig. 4. Docking models of silanol 5a and 5f with hERβ LBD (PDB ID: 3OLS) obtained with AutoDock 4.2. The protein surface is indicated as a blue mesh. (Left) Docking model of 5a (yellow) in the hERβ LBD. (Center) Docking model of 5f (cyan) in the hERβ LBD. (Right) Superimposition of the docking models of 5a and 5f.
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