title: Synthesis and biological evaluation of phenolic 4,5-dihydroisoxazoles and 3-hydroxy ketones as estrogen receptor alpha and beta agonists.
abstract: In this work, 52 diphenyl-4,5-dihydroisoxazoles and -3-hydroxy ketones were prepared and their estrogen receptor alpha (ERalpha) and estrogen receptor beta (ERbeta) activities were explored in order to systematize and maximize their biological activity. The biological activity was firstly screened by using ERE reporter assay to find out how aromatic hydroxylation and methylation of the chiral centers of the compounds affect the ability of ER to mediate biological responses. For selected 19 compounds, the relative binding affinities (RBA, relative to 3,17beta-estradiol) and ability to induce transcription of primary E2 target gene pS2 in human MCF-7 breast cancer cells were determined. In the reporter assay, many compounds showed even stronger activity than E2 and some of them showed RBA larger than 1%. The highest RBAs were determined for the enantiomers of 1-hydroxy-6-(4-hydroxy-phenyl)-1-phenyl-hexan-3-one (50a and 50b). Isomer 50a showed high binding affinity both to ERalpha (with RBA approximately 200%) and ERbeta (with RBA approximately 60%), while the RBAs of 50b were ca. 40% of those. Some of the other compounds (with RBA approximately 1-16%) showed also notable ERalpha binding selectivity. When four most promising ligands (50a, 50b, 45a, and 45b) were studied with respect to their ability to induce the transcription of primary E2 target gene pS2, the compounds acted as agonists or partial agonists. Computer modeling was used to predict receptor binding conformations and to rationalize the RBA differences of the compounds.
authors.affiliation: Laboratory of Chemistry, Department of Biosciences, University of Eastern Finland, PO Box 1627, FIN-70211 Kuopio, Finland.
authors.forename: Pekka K
authors.initials: PK
authors.lastname: Poutiainen
authors.forename: Tuomas A
authors.initials: TA
authors.lastname: Venäläinen
authors.forename: Mikael
authors.initials: M
authors.lastname: Peräkylä
authors.forename: Juha M
authors.initials: JM
authors.lastname: Matilainen
authors.forename: Sami
authors.initials: S
authors.lastname: Väisänen
authors.forename: Paavo
authors.initials: P
authors.lastname: Honkakoski
authors.forename: Reino
authors.initials: R
authors.lastname: Laatikainen
authors.forename: Juha T
authors.initials: JT
authors.lastname: Pulkkinen
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000819:agonists*; D047629:Estrogen Receptor beta / Q000819:agonists*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D007659:Ketones / Q000138:chemical synthesis* / Q000494:pharmacology; D008968:Molecular Conformation; D010636:Phenols / Q000138:chemical synthesis / Q000494:pharmacology*; D011485:Protein Binding; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D007555:Isoxazoles; D007659:Ketones; D010636:Phenols; D004958:Estradiol