title: 4,4'-Unsymmetrically substituted 3,3'-biphenyl alpha helical proteomimetics as potential coactivator binding inhibitors.
abstract: A series of unsymmetrically substituted biphenyl compounds was designed as alpha helical proteomimetics with the aim of inhibiting the binding of coactivator proteins to the nuclear hormone receptor coactivator binding domain. These compounds were synthesized in good overall yields in seven steps starting from 2-bromoanisole. The final products were evaluated using cotransfection reporter gene assays and mammalian two-hybrid competitive inhibition assays to demonstrate their effectiveness as competitive binding inhibitors. The results from this study indicate that these proteomimetics possess the ability to inhibit coactivator-receptor interactions, but via a mixed mode of inhibition.
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Ave., Boston, MA 02115, USA.
authors.forename: Patrick T
authors.initials: PT
authors.lastname: Weiser
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Ching-Yi
authors.initials: CY
authors.lastname: Chang
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Donald P
authors.initials: DP
authors.lastname: McDonnell
authors.affiliation: Department of Chemistry and Chemical Biology, Northeastern University, 360 Huntington Ave., Boston, MA 02115, USA. Electronic address: r.hanson@neu.edu.
authors.forename: Robert N
authors.initials: RN
authors.lastname: Hanson
mesh_terms: D001667:Binding, Competitive / Q000187:drug effects; D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D056945:Hep G2 Cells; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D056918:Nuclear Receptor Coactivators / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D017433:Protein Structure, Secondary; D013329:Structure-Activity Relationship
chemical_list: D001713:Biphenyl Compounds; D056918:Nuclear Receptor Coactivators
keywords: Co-activator binding inhibition; Nuclear receptor; Proteomimetic