title: Characterization of five 19-nor-analogs of 1alpha,25(OH)2-Vitamin D3 with 20-cyclopropyl-modified side-chains: implications for ligand binding and calcemic properties.
abstract: The steroid hormone 1alpha,25(OH)(2)-Vitamin D(3) [1alpha,25(OH)(2)D(3)] exerts a wide variety of biological actions through one or more receptors/binding proteins. The nuclear Vitamin D receptor (VDR) when bound to its natural ligand, 1alpha,25(OH)(2)D(3), can stimulate transcription of a wide variety of genes. The synthesis of 1alpha,25(OH)(2)D(3) analogs allows the study of structure-function relationships between ligand and the VDR. 1alpha,25(OH)(2)D(3) is a conformationally flexible molecule; specifically the side-chain of the hormone can display a large variety of shapes for its receptor. Here, we describe and analyze the properties of 10 1alpha,25(OH)(2)D(3) analogs modified at the side-chain of which five lack carbon-19 (19-nor) but have a novel 20-cyclopropyl functionality. Analog NG [20,21-methylene-23-yne-26,27-F(6)-19-nor-1alpha,25(OH)(2)D(3)] possesses a respectable binding affinity for the VDR and exhibits a high transcriptional activity (EC(50) approximately 10pM), while retaining low induction of hypercalcemia in vivo in the mouse, making it a primary candidate for further analyses of its anti-proliferative and/or cell differentiating properties.
authors.affiliation: Department of Biochemistry, University of California, Riverside, CA 92521, USA.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Olivera
authors.forename: Craig M
authors.initials: CM
authors.lastname: Bula
authors.forename: June E
authors.initials: JE
authors.lastname: Bishop
authors.forename: Luciano
authors.initials: L
authors.lastname: Adorini
authors.forename: Percy
authors.initials: P
authors.lastname: Manchand
authors.forename: Milan R
authors.initials: MR
authors.lastname: Uskokovic
authors.forename: Anthony W
authors.initials: AW
authors.lastname: Norman
mesh_terms: D000818:Animals; D019556:COS Cells; D002117:Calcitriol / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000097:blood*; D005260:Female; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D011485:Protein Binding; D011487:Protein Conformation; D018167:Receptors, Calcitriol / Q000378:metabolism
chemical_list: D008024:Ligands; D018167:Receptors, Calcitriol; D002117:Calcitriol; D002118:Calcium