title: 6-arylcoumarins as novel nonsteroidal type progesterone antagonists: an example with receptor-binding-dependent fluorescence.
abstract: Various 6-arylcoumarin derivatives were designed and synthesized as candidate nonsteroidal type progesterone antagonists. 6-Bromocoumarin derivatives were prepared from the corresponding 4-substituted 2-acetoxy-5-bromobenzaldehyde by employing the Still-Gennari modification of the Horner-Wadsworth-Emmons olefination reaction and were converted to 6-arylcoumarins by means of Suzuki-Miyaura cross-coupling reactions. The biological activities of these coumarin derivatives were evaluated by means of alkaline phosphatase assay in the T47D human breast carcinoma cell line. Among the synthesized compounds, 36 (IC(50) = 0.12 μM) and 38 (IC(50) = 0.065 μM), bearing a five-membered heterocycle, showed potent PR antagonist activity. Competitive binding assay showed that compounds 8 and 34 have potent PR binding affinity. The fluorescence of compound 8 was dependent on the solvent properties and was increased in the presence of PR ligand binding domain. This property might be applicable to the development of fluorescence probes for studies on PR.
authors.affiliation: Department of Chemistry, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Sakai
authors.forename: Tomoya
authors.initials: T
authors.lastname: Hirano
authors.forename: Shuichi
authors.initials: S
authors.lastname: Mori
authors.forename: Shinya
authors.initials: S
authors.lastname: Fujii
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Masuno
authors.forename: Marie
authors.initials: M
authors.lastname: Kinoshita
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
authors.forename: Aya
authors.initials: A
authors.lastname: Tanatani
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D016466:CHO Cells; D045744:Cell Line, Tumor; D003374:Coumarins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D005453:Fluorescence; D005456:Fluorescent Dyes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D011374:Progesterone / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000819:agonists / Q000037:antagonists & inhibitors*; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012997:Solvents; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation
chemical_list: D003374:Coumarins; D005456:Fluorescent Dyes; D008024:Ligands; D011980:Receptors, Progesterone; D011994:Recombinant Proteins; D012997:Solvents; D011374:Progesterone; D000469:Alkaline Phosphatase