title: Synthesis of vitamin D3 derivatives with nitrogen-linked substituents at A-ring C-2 and evaluation of their vitamin D receptor-mediated transcriptional activity.
abstract: Binding of a series of novel 1α,25-dihydroxyvitamin D(3) (1,25-VD(3)) derivatives, having a nitrogen-linked substituent at the 2α- or 2β-position of the A-ring (2-N-substituted compounds), with the vitamin D receptor (VDR) was investigated by means of computational docking studies. Selected compounds were synthesized by coupling A-ring synthons  and/or  with CD-ring-bearing bromomethylene  under Trost's conditions. The 2α- and 2β-stereoisomers of the A-ring synthons were synthesized from l-serine () as a single chiral source by installing vinyl and propargyl groups at opposite ends of the molecule. The activity of the obtained compounds was evaluated by means of a luciferase-based VDR transcriptional activity assay in NIH3T3 cells. Relatively small substituents incorporating a hydrogen-bonding donor, i.e., NHAc and NHMs, were effective for eliciting VDR transcriptional activity, and 2β-NHMs-1,25-VD(3) () showed the highest activity, being more potent than 1,25-VD(3). Derivatives with bulky substituents were inactive. These new insights into the structure-activity relationships of 1,25-VD(3) derivatives may be helpful in separating the various biological activities of 1,25-VD(3) and in generating novel therapeutic drug candidates.
authors.affiliation: Department of Biotechnology and Life Science, Faculty of Technology, Tokyo University of Agriculture and Technology, 2-24-16 Naka-cho, Koganei, Tokyo 184-8588, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Abe
authors.forename: Yu
authors.initials: Y
authors.lastname: Nagai
authors.forename: Rui
authors.initials: R
authors.lastname: Higashikuni
authors.forename: Keisuke
authors.initials: K
authors.lastname: Iida
authors.forename: Takatsugu
authors.initials: T
authors.lastname: Hirokawa
authors.forename: Hazuki
authors.initials: H
authors.lastname: Nagai
authors.forename: Kaichiro
authors.initials: K
authors.lastname: Kominato
authors.forename: Toshio
authors.initials: T
authors.lastname: Tsuchida
authors.forename: Michiko
authors.initials: M
authors.lastname: Hirata
authors.forename: Masaki
authors.initials: M
authors.lastname: Inada
authors.forename: Chisato
authors.initials: C
authors.lastname: Miyaura
authors.forename: Kazuo
authors.initials: K
authors.lastname: Nagasawa
mesh_terms: D002762:Cholecalciferol / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism*; D008958:Models, Molecular; D008968:Molecular Conformation; D009584:Nitrogen / Q000737:chemistry*; D018167:Receptors, Calcitriol / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D018167:Receptors, Calcitriol; D002762:Cholecalciferol; D009584:Nitrogen