title: Removal of the 26-methyl group from 19-nor-1α,25-dihydroxyvitamin D₃ markedly reduces in vivo calcemic activity without altering in vitro VDR binding, HL-60 cell differentiation, and transcription.
abstract: Twelve new analogues of 19-nor-1α,25-dihydroxyvitamin D₃ (5-16) were prepared by convergent syntheses, employing the Wittig-Horner reaction. The necessary Grundmann type ketones (45-48), possessing fixed configurations of the hydroxyl group at C-25, were obtained by a multistep procedure from commercial vitamin D₂ and enantiomers of 1,3-butanediol (23 and 24). We have examined the influence of removal of one of the methyl groups located at C-25 on the biological in vitro and in vivo activity. The in vivo tests showed that the synthesized vitamin D compounds (5-16) exhibit reduced calcemic activity both in bone and in the intestine. However, in vitro potency of 2-methylene and 2α-methyl compounds (5-10, 13, and 14) remained similar or enhanced as compared to that of 1α,25-(OH)₂D₃.
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, Madison, Wisconsin 53706, USA.
authors.forename: Pawel
authors.initials: P
authors.lastname: Grzywacz
authors.forename: Grazia
authors.initials: G
authors.lastname: Chiellini
authors.forename: Lori A
authors.initials: LA
authors.lastname: Plum
authors.forename: Margaret
authors.initials: M
authors.lastname: Clagett-Dame
authors.forename: Hector F
authors.initials: HF
authors.lastname: DeLuca
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001692:Biological Transport; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism*; D013237:Stereoisomerism; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C555222:19-nor-1,25-dihydroxyvitamin D3; D018167:Receptors, Calcitriol; D002117:Calcitriol; D002118:Calcium