title: Design and synthesis of novel ROR inverse agonists with a dibenzosilole scaffold as a hydrophobic core structure.
abstract: Molecular structure calculations indicated that the dibenzosilole skeleton could be well superposed on phenanthridinone, which is a structural component of ligands of retinoic acid receptor-related orphan receptors (RORs). Therefore, we designed, synthesized and biologically evaluated a series of novel ROR ligands based on the dibenzosilole scaffold as a hydrophobic core structure. Dibenzosilole derivatives bearing a hexafluoro-2-hydroxypropyl group on the benzene ring exhibited significant ROR-inhibitory activity, comparable to that of the lead phenanthridinone derivative 5. Our results indicate that the dibenzosilole skeleton would be a useful scaffold for developing novel biologically active compounds, and that cis-amide structure can be replaced by an alkylsilyl functionality.
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, 113-0032 Tokyo, Japan.
authors.forename: Hirozumi
authors.initials: H
authors.lastname: Toyama
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, 113-0032 Tokyo, Japan.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, 113-0032 Tokyo, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, 113-0032 Tokyo, Japan. Electronic address: fujiis@iam.u-tokyo.ac.jp.
authors.forename: Shinya
authors.initials: S
authors.lastname: Fujii
mesh_terms: D001555:Benzene Derivatives / Q000138:chemical synthesis* / Q000737:chemistry; D001665:Binding Sites; D015195:Drug Design; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000819:agonists* / Q000737:chemistry; D017646:Organosilicon Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D010617:Phenanthridines / Q000138:chemical synthesis* / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D001555:Benzene Derivatives; D008024:Ligands; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D017646:Organosilicon Compounds; D010617:Phenanthridines; C539900:RORC protein, human
keywords: Dibenzosilole; ROR; Retinoic acid receptor-related orphan receptor; Sila-substitution