title: 2-Methylene analogs of 1alpha-hydroxy-19-norvitamin D3: synthesis, biological activities and docking to the ligand binding domain of the rat vitamin D receptor.
abstract: In continuing efforts towards the synthesis of biologically active vitamin D compounds of potential therapeutic value, new 2-methylene-1alpha-hydroxy-19-norvitamin D(3) analogs 3 and 4 with modified alkyl side chains have been synthesized. The key synthetic step involved Lythgoe-type Wittig-Horner coupling of Windaus-Grundmann type ketones 9, possessing different 17beta-alkyl substituents, with the phosphine oxide 10 prepared from (-)-quinic acid. The prepared vitamins 3 and 4 were ca. eight times less potent than 1alpha,25-dihydroxyvitamin D(3) (1alpha,25-(OH)(2)D(3)) (1) in binding to the rat intestinal vitamin D receptor (VDR). In comparison with the hormone 1 they exhibited slightly lower cellular HL-60 differentiation activity. When tested in vivo; the analog 3 was characterized by very high bone calcium mobilizing potency and intestinal calcium transport activity. Unexpectedly, the 25-methyl compound 4 showed marked calcemic activity in both assays. Computational docking of the vitamin 3 into the binding pocket of the rat vitamin D receptor is also reported.
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA.
authors.forename: Pawel
authors.initials: P
authors.lastname: Grzywacz
authors.forename: Lori A
authors.initials: LA
authors.lastname: Plum
authors.forename: Wanda
authors.initials: W
authors.lastname: Sicinska
authors.forename: Rafal R
authors.initials: RR
authors.lastname: Sicinski
authors.forename: Jean M
authors.initials: JM
authors.lastname: Prahl
authors.forename: Hector F
authors.initials: HF
authors.lastname: DeLuca
mesh_terms: D000818:Animals; D001665:Binding Sites; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D006838:Hydrocarbons; D008024:Ligands; D008697:Methane / Q000031:analogs & derivatives* / Q000737:chemistry*; D051379:Mice; D008958:Models, Molecular; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism*
chemical_list: C114865:1-hydroxy-19-norvitamin D3; D006838:Hydrocarbons; D008024:Ligands; D018167:Receptors, Calcitriol; C030011:carbene; D002117:Calcitriol; D008697:Methane