title: Structure-activity relationships of 19-norvitamin D analogs having a fluoroethylidene group at the C-2 position.
abstract: We have synthesized four new geometric isomers of 1alpha,25-dihydroxy-2-(2'-fluoroethylidene)-19-norvitamin D analogs 1 and 2 having a 20R- and 20S-configuration, whose structures are correlated with 2MD possessing high potencies in stimulating bone formation in vitro and in vivo. The E-isomers of (20R)- and (20S)-2-fluoroethylidene analogs 1a and 1b were comparable with the natural hormone 1alpha,25-(OH)(2)D(3) in binding to the vitamin D receptor (VDR), while two Z-isomers 2a and 2b were about 15-20 times less active than the hormone. In inducing expression of the vitamin D responsive element-based luciferase reporter gene, the E-isomers 1a and 1b were 1.2- and 8.6-fold more potent than the hormone, respectively, while the Z-isomers 2a and 2b had 27-55% of the potency. On the basis of the biological activities and a docking simulation based on X-ray crystallographic analysis of the VDR ligand-binding pocket, the structure-activity relationships of the fluorinated 19-norvitamin D analogs are discussed.
authors.affiliation: Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Emi
authors.initials: E
authors.lastname: Kobayashi
authors.forename: Mika
authors.initials: M
authors.lastname: Shimazaki
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Masuno
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Hector F
authors.initials: HF
authors.lastname: DeLuca
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamada
authors.forename: Masato
authors.initials: M
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D001665:Binding Sites; D019556:COS Cells / Q000187:drug effects; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D051379:Mice; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D018167:Receptors, Calcitriol / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic; D014753:Vinyl Compounds / Q000737:chemistry; D030181:Vitamin D Response Element / Q000235:genetics
chemical_list: D018167:Receptors, Calcitriol; C506896:Spp1 protein, mouse; D014753:Vinyl Compounds; D053495:Osteopontin; C083610:1,25-dihydroxy-19-norvitamin D3; C016829:vinyl fluoride; D002117:Calcitriol