title: Synthesis and structure-activity relationships of 16-ene-22-thia-1alpha,25-dihydroxy-26,27-dimethyl-19-norvitamin D3 analogs having side chains of different sizes.
abstract: We have synthesized eight novel 16-ene-22-thia-26,27-dimethyl-19-norvitamin D3 analogs 1-5 bearing side chains of different sizes, in combination with 20S- and 20R-isomers. The target compounds were prepared by Wittig-Horner reaction of A-ring phosphine oxide with 16-ene-22-thia-25-hydroxy Grundmann's ketones having different sized side chains, which were derived from the S-phenyloxycarbonyl derivative 13 as key intermediates. The binding affinity to the vitamin D receptor (VDR), VDR-mediated transcriptional activity, and osteoclast-inducing activity of synthetic 22-thia-19-norvitamin D analogs 1-5 were investigated. The (20S)-22-thia-19,24-dinorvitamin D analog 1a is as active as the natural hormone 1alpha,25-dihydroxyvitamin D3 (1alpha,25-(OH)2D3) in terms of biological activities tested in vitro. The analogs 2a and 3a exhibited almost the same potency as 1alpha,25-(OH)2D3 in binding to the VDR, were about 20 times more potent than 1alpha,25-(OH)2D3 in terms of transcriptional activity, and 3a was approximately 100 times as potent as 1alpha,25-(OH)2D3 in eliciting osteoclast formation. The biological activities of (20S)-22-thia compounds were more potent (by more than 10-fold) than those of the corresponding 20R-counterparts, but the activity of (20R)-compounds 1b, 2b, and 3b in stimulating the formation of osteoclasts was similar to that of 1alpha,25-(OH)2D3, and the 24-dihomo- and trihomo-analogs 4a and 5a showed low transcriptional activity. These results suggest that elongation of the side chain in 22-thia analogs by up to one carbon can be stably accommodated in the VDR ligand binding pocket.
authors.affiliation: Laboratory of Medicinal Chemistry, School of Biomedical Science, Tokyo Medical and Dental University, 2-3-10 Kanda-Surugadai, Chiyoda-ku, Tokyo 101-0062, Japan.
authors.forename: Hajime
authors.initials: H
authors.lastname: Takaku
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Shiori
authors.initials: S
authors.lastname: Asami
authors.forename: Mika
authors.initials: M
authors.lastname: Shimazaki
authors.forename: Sachiko
authors.initials: S
authors.lastname: Yamada
authors.forename: Keiko
authors.initials: K
authors.lastname: Yamamoto
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Udagawa
authors.forename: Hector F
authors.initials: HF
authors.lastname: DeLuca
authors.forename: Masato
authors.initials: M
authors.lastname: Shimizu
mesh_terms: D001665:Binding Sites; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D010010:Osteoclasts / Q000187:drug effects; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000378:metabolism; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D018167:Receptors, Calcitriol; D002762:Cholecalciferol