title: Synthesis of 14-epi-2α-hydroxypropoxy-1α,25-dihydroxy-19-nortachysterol and its hVDR binding.
abstract: Recently, we evaluated a novel skeleton in the vitamin D family, 14-epi-1α,25(OH)2-19-nortachysterol, and discovered its unique binding configuration in the human vitamin D receptor (VDR) with the C5,6- and C7,8-s-trans triene configuration. Because of its unprecedented form, this skeleton has a promising characteristic profile for clinical use, and also the synthesis of its derivatives should be versatile. Therefore, we synthesized the novel analog, 2α-hydroxypropoxy substituted 14-epi-1α,25(OH)2-19-nortachysterol, and evaluated its human VDR binding affinity. Although this substitution is one of the promising modification of vitamin D3 such as eldecalcitol (ED-71), it had negative effects on the binding affinity, and the compound showed lower affinity than 1α,25(OH)2D3 and its parent compound, 14-epi-1α,25(OH)2-19-nortachysterol. It was thought that the unprecedented binding configuration of this skeleton should not allow the terminal hydroxyl group of the 2α-substituent to construct effective hydrogen bond networks around the amino acid residues in the binding pocket. This article is part of a Special Issue entitled 'Vitamin D Workshop'.
authors.affiliation: Faculty of Pharmaceutical Sciences, Teikyo University, 2-11-1, Kaga, Itabashi, Tokyo 173-8605, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Sawada
authors.forename: Yuya
authors.initials: Y
authors.lastname: Tsukuda
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Saito
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Takagi
authors.forename: Shinji
authors.initials: S
authors.lastname: Kakuda
authors.forename: Midori
authors.initials: M
authors.lastname: Takimoto-Kamimura
authors.forename: Eiji
authors.initials: E
authors.lastname: Ochiai
authors.forename: Kazuya
authors.initials: K
authors.lastname: Takenouchi
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kittaka
mesh_terms: D001665:Binding Sites; D060326:Chemistry Techniques, Synthetic; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism; D004353:Drug Evaluation, Preclinical; D006801:Humans; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C583150:14-epi-2alpha-hydroxypropoxy-1alpha,25-dihydroxy-19-nortachysterol; D018167:Receptors, Calcitriol; D002762:Cholecalciferol