title: Development of silicon-containing bis-phenol derivatives as androgen receptor antagonists: selectivity switching by C/Si exchange.
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.
authors: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan. nakamura-nk@iam.u-tokyo.ac.jp
authors: Masaharu
authors: M
authors: Nakamura
authors: Makoto
authors: M
authors: Makishima
authors: Yuichi
authors: Y
authors: Hashimoto
mesh_terms: D059002:Androgen Receptor Antagonists / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D019800:Phenol / Q000737:chemistry* / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000378:metabolism; D012825:Silicon / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D059002:Androgen Receptor Antagonists; D011944:Receptors, Androgen; D018167:Receptors, Calcitriol; D019800:Phenol; D012825:Silicon