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  • Development of silicon-containing bis-phenol derivatives as androgen receptor antagonists: selectivity switching by C/Si exchange.

Development of silicon-containing bis-phenol derivatives as androgen receptor antagonists: selectivity switching by C/Si exchange.

Bioorganic & medicinal chemistry (2013-03-07)
Masaharu Nakamura, Makoto Makishima, Yuichi Hashimoto
ABSTRACT

We previously reported that bis-phenol derivatives, including LG190178 (3a), possess not only vitamin D receptor (VDR) agonistic activity, but also androgen receptor (AR) antagonistic activity. Here, we describe the design, synthesis and evaluation of silicon-containing bis-phenol derivatives, with the objective of obtaining increased selectivity toward VDR or AR. We found that replacement of the quaternary carbon in the bis-phenol skeleton with silicon increased AR-antagonistic activity and reduced VDR-agonistic activity, that is, the AR selectivity of the silicon-containing compounds was higher than that of corresponding carbon compounds. To our knowledge, this is the first report of nuclear receptor (NR) selectivity switching by sila-substitution (C/Si exchange). Among the compounds synthesized, AR-selective ligand (S,R)-3b exhibited more potent anti-androgenic activity (IC50=0.072 μM) than hydroxyflutamide, a well-known androgen antagonist (IC50=1.4 μM), in SC-3 cell proliferation assay. These results suggest that sila-substitution is a useful approach for structural development of selective AR ligands.

MATERIALS
Product Number
Brand
Product Description

Supelco
Phenol, Pharmaceutical Secondary Standard; Certified Reference Material
Sigma-Aldrich
Phenol, unstabilized, ReagentPlus®, ≥99%
Sigma-Aldrich
Phenol, unstabilized, purified by redistillation, ≥99%
Sigma-Aldrich
Phenol, ≥96.0% (calc. on dry substance, T)
Sigma-Aldrich
Phenol, BioUltra, for molecular biology, ≥99.5% (GC)
Sigma-Aldrich
Phenol, puriss., meets analytical specification of Ph. Eur., BP, USP, ≥99.5% (GC), crystalline (detached)
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Phenol, puriss., meets analytical specification of Ph. Eur., BP, USP, 99.5-100.5% (GC)
Sigma-Aldrich
Phenol, BioUltra, for molecular biology, TE-saturated, ~73% (T)
Sigma-Aldrich
Phenol, puriss. p.a., ACS reagent, reag. Ph. Eur., 99.0-100.5%
Sigma-Aldrich
Phenol, contains hypophosphorous as stabilizer, loose crystals, ACS reagent, ≥99.0%
Supelco
Phenol solution, certified reference material, 500 μg/mL in methanol
Supelco
Phenol solution, 5000 μg/mL in methanol, certified reference material
Supelco
Phenol solution, 100 μg/mL in acetonitrile, PESTANAL®, analytical standard
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Phenol, for molecular biology
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Phenol, BioXtra, ≥99.5% (GC)
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Phenol solution, Equilibrated with 10 mM Tris HCl, pH 8.0, 1 mM EDTA, BioReagent, for molecular biology
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Phenol solution, BioReagent, Saturated with 0.01 M citrate buffer, pH 4.3 ± 0.2, for molecular biology
Sigma-Aldrich
Liquified Phenol, ≥89.0%
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Phenol, ≥99%
Supelco
Phenol, PESTANAL®, analytical standard