title: Ligands with a 3,3-diphenylpentane skeleton for nuclear vitamin D and androgen receptors: Dual activities and metabolic activation.
abstract: Ligands possessing dual vitamin D(3) (VD(3))-agonistic and androgen-antagonistic activities with various activity spectra were prepared based on a substituted 3,3-diphenylpentane (DPP) skeleton. Among the compounds, (R,S)-DPP-1023 [(R,S)-7b] and (S,S)-DPP-0123 [(S,S)-7c] showed the most potent vitamin D(3)-agonistic activity [with potency comparable to that of 1alpha,25-dihydroxyvitamin D(3) (1,25-VD(3))] and nuclear androgen receptor (AR)-binding activity (with higher affinity than that of hydroxyflutamide), respectively. Metabolic activation (reduction of the carbonyl group) of pivaloyl analogs [DPP-1113 (3a), DPP-1013 (3b), DPP-0113 (3c), and DPP-0013 (3d)] in HL-60 cells was found to be necessary for binding to nuclear vitamin D(3) receptor (VDR).
authors.affiliation: Institute of Molecular and Cellular Biosciences, The University of Tokyo, Bunkyo-ku, Japan. ff46027@mail.ecc.u-tokyo.ac.jp
authors.forename: Shinnosuke
authors.initials: S
authors.lastname: Hosoda
authors.forename: Aya
authors.initials: A
authors.lastname: Tanatani
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Wakabayashi
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
authors.forename: Keisuke
authors.initials: K
authors.lastname: Imai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Miyachi
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nagasawa
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Hashimoto
mesh_terms: D059002:Androgen Receptor Antagonists; D001559:Benzhydryl Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D001665:Binding Sites; D049109:Cell Proliferation / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D018922:HL-60 Cells; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011944:Receptors, Androgen / Q000378:metabolism*; D014807:Vitamin D / Q000819:agonists / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D014809:Vitamin D-Binding Protein / Q000378:metabolism
chemical_list: D059002:Androgen Receptor Antagonists; D001559:Benzhydryl Compounds; D008024:Ligands; D011944:Receptors, Androgen; D014809:Vitamin D-Binding Protein; C118756:dihydroxy-vitamin D3; D014807:Vitamin D