title: Estrogenic activity of bis(4-hydroxyphenyl)methanes with cyclic hydrophobic structure.
abstract: Monoalkylated bis(4-hydroxyphenyl)methanes (e.g., 1) are reported to show weak binding affinity for estrogen receptor (ER). We hypothesized that introduction of appropriately located hydrophobic substituents in these compounds would increase the binding affinity. Indeed, we found that bis(4-hydroxyphenyl)methane bearing a 3,3-dimethylcyclohexyl group (7) shows potent ERα binding affinity, comparable to that of estradiol. Bulkier substituents could be introduced at the 3,3-position without decreasing the affinity. However, the position of the substituents was critical: the 4,4-dimethylcyclohexyl derivative (2) showed very weak binding affinity. The compounds with high ER-binding affinity showed predominantly agonistic activity, together with weak antagonistic activity at high concentration, in cell proliferation assay with human breast cancer cell line MCF-7. Further structure-function studies of these compounds and their derivatives might lead to the development of more selective and potent estrogen receptor modulators.
authors.affiliation: Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kojima
authors.affiliation: Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
authors.forename: Takumi
authors.initials: T
authors.lastname: Ogawa
authors.affiliation: Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
authors.forename: Souichiro
authors.initials: S
authors.lastname: Kitao
authors.affiliation: Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Sato
authors.affiliation: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan; Institute for Protein Research, Osaka University, 3-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
authors.forename: Akifumi
authors.initials: A
authors.lastname: Oda
authors.affiliation: Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
authors.forename: Kiminori
authors.initials: K
authors.lastname: Ohta
authors.affiliation: Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. Electronic address: yendo@tohoku-pharm.ac.jp.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Endo
mesh_terms: D001559:Benzhydryl Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects; D004958:Estradiol / Q000737:chemistry / Q000378:metabolism; D020847:Estrogen Receptor Modulators / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D061986:MCF-7 Cells; D062105:Molecular Docking Simulation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D013329:Structure-Activity Relationship; D000098833:Bisphenol F Compounds
chemical_list: D001559:Benzhydryl Compounds; D004958:Estradiol; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; C008745:4,4'-bisphenol F; D000098833:Bisphenol F Compounds
keywords: Carborane; Estrogen receptor; Partial agonist; SERM