title: Design and synthesis of tetraol derivatives of 1,12-dicarba-closo-dodecaborane as non-secosteroidal vitamin D analogs.
abstract: Vitamin D receptor (VDR), a nuclear receptor for 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3, 1), is a promising target for multiple clinical applications. We recently developed non-secosteroidal VDR ligands based on a carbon-containing boron cluster, 1,12-dicarba-closo-dodecaborane (p-carborane), and examined the binding of one of them to VDR by means of crystallographic analysis. Here, we utilized that X-ray structure to design novel p-carborane-based tetraol-type vitamin D analogs, and we examined the biological activities of the synthesized compounds. Structure-activity relationship study revealed that introduction of an ω-hydroxyalkoxy functionality enhanced the biological activity, and the configuration of the substituent significantly influenced the potency. Among the synthesized compounds, 4-hydroxybutoxy derivative 9a exhibited the most potent activity, which was equal to that of the secosteroidal vitamin D analog, 19-nor-1α,25-dihydroxyvitamin D3 (2).
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan; Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-0032, Japan.
authors.forename: Shinya
authors.initials: S
authors.lastname: Fujii
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kano
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Masuno
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Kho-Hong, Hat Yai, Songkhla 90112, Thailand.
authors.forename: Chalermkiat
authors.initials: C
authors.lastname: Songkram
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Kawachi
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Hirano
authors.affiliation: Department of Chemistry, Faculty of Science, Ochanomizu University, 2-1-1 Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan.
authors.forename: Aya
authors.initials: A
authors.lastname: Tanatani
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan. Electronic address: kage.chem@tmd.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
mesh_terms: D001896:Boron Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015195:Drug Design; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D018167:Receptors, Calcitriol / Q000378:metabolism*; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: C000596675:1,12-dicarba-closo-dodecaborane; D001896:Boron Compounds; D008024:Ligands; D018167:Receptors, Calcitriol; D014807:Vitamin D
keywords: Carborane; Non-secosteroid; Nuclear receptor; Vitamin D