title: The 2alpha-(3-hydroxypropyl) group as an active motif in vitamin D3 analogues as agonists of the mutant vitamin D receptor (Arg274Leu).
abstract: We designed and synthesized 1alpha- and 1beta-hydroxymethyl-2alpha-(3-hydroxypropyl)-25-hydroxyvitamin D(3) (2a,b) and related analogues 2alpha-(3-hydroxypropyl)-25-hydroxyvitamin D(3) (3), Posner's analogues of 1alpha- and 1beta-hydroxymethyl-25-hydroxyvitamin D(3) (4a,b), as well as 2alpha-(3-hydroxypropyl)-1alpha,25-dihydroxyvitamin D(3) (5), to confirm the effect of the 1alpha-hydroxy group and/or 2alpha-(3-hydroxypropyl) group of vitamin D(3) analogues with the modified A-ring moiety on the mutant vitamin D receptor, VDR(Arg274Leu). The 2alpha-(3-hydroxypropyl) group showed better effect on enhancement of the transcriptional activity through the mutant VDR than the 1alpha- and 1beta-hydroxymethyl groups.
authors.affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Teikyo University, Kanagawa 229-0195, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Honzawa
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Yamashita
authors.forename: Takayuki
authors.initials: T
authors.lastname: Sugiura
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kurihara
authors.forename: Midori A
authors.initials: MA
authors.lastname: Arai
authors.forename: Shigeaki
authors.initials: S
authors.lastname: Kato
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
mesh_terms: D002762:Cholecalciferol / Q000031:analogs & derivatives*; D015195:Drug Design; D006801:Humans; D050505:Mutant Proteins / Q000819:agonists*; D020125:Mutation, Missense; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000235:genetics*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D050505:Mutant Proteins; D018167:Receptors, Calcitriol; D002762:Cholecalciferol