title: Synthesis, Biological Activities, and X-ray Crystal Structural Analysis of 25-Hydroxy-25(or 26)-adamantyl-17-[20(22),23-diynyl]-21-norvitamin D Compounds.
abstract: Novel 19-norvitamin D analogues (ADYW1-4, 5a-d) in which an adamantyl diyne side chain is attached directly to the 17-position of the D ring are designed and stereoselectively synthesized. The adamantane ring of these analogues was expected to interfere with helix 12 (H12, activation function 2) of the vitamin D receptor (VDR) to modulate its activities. The analogue 5b binds to the VDR (7% of the natural hormone) and shows significant partial agonistic activity in transactivation assay. Compound 5b showed considerable selectivity in VDR target genes expressions in vitro, it was taken up by target cells 2-3 times more readily, and its lifetime was three times longer than the natural hormone. The X-ray crystal structure of 5b in complex with VDR reveals that the ligand binds similarly to the natural hormone, but the diyne moiety is slightly bent (angles around the diyne 5° to 8°) with respect to the original diyne vitamin D compound 6 in VDR (<1°) due to steric hindrance with helix 12.
authors.affiliation: Department of Chemistry, Faculty of Science, Rikkyo University , Toshima-ku, Tokyo 171-8501, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Watarai
authors.affiliation: Department of Biomedical Sciences, Nihon University School of Medicine , 30-1 Ohyaguchikami-machi, Itabashi-ku, Tokyo 173-8610, Japan.
authors.forename: Michiyasu
authors.initials: M
authors.lastname: Ishizawa
authors.affiliation: Medical Research Institute, Tokyo Medical and Dental University , Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Teikichi
authors.initials: T
authors.lastname: Ikura
authors.affiliation: Departamento de Química Orgánica, Laboratorio de Investigación Ignacio Ribas, Universidad de Santiago de Compostela , 15782 Santiago de Compostela, Spain.
authors.forename: Flavia C M
authors.initials: FC
authors.lastname: Zacconi
authors.affiliation: Department of Biomedical Sciences, Nihon University School of Medicine , 30-1 Ohyaguchikami-machi, Itabashi-ku, Tokyo 173-8610, Japan.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Uno
authors.affiliation: Medical Research Institute, Tokyo Medical and Dental University , Bunkyo-ku, Tokyo 113-8510, Japan.
authors.forename: Nobutoshi
authors.initials: N
authors.lastname: Ito
authors.affiliation: Departamento de Química Orgánica, Laboratorio de Investigación Ignacio Ribas, Universidad de Santiago de Compostela , 15782 Santiago de Compostela, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Mouriño
authors.affiliation: Department of Chemistry, Faculty of Science, Rikkyo University , Toshima-ku, Tokyo 171-8501, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Tokiwa
authors.affiliation: Department of Biomedical Sciences, Nihon University School of Medicine , 30-1 Ohyaguchikami-machi, Itabashi-ku, Tokyo 173-8610, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Makishima
authors.affiliation: Department of Biomedical Sciences, Nihon University School of Medicine , 30-1 Ohyaguchikami-machi, Itabashi-ku, Tokyo 173-8610, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamada
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D054333:Drug Partial Agonism; D057809:HEK293 Cells; D006801:Humans; D015394:Molecular Structure; D009928:Organ Specificity; D018167:Receptors, Calcitriol / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation
chemical_list: C000607189:ADYW2 compound; D018167:Receptors, Calcitriol; D002117:Calcitriol; D000218:Adamantane