title: An analog of 1alpha,25-dihydroxy-19-norvitamin D3 with the 1alpha-hydroxy group fixed in the axial position lacks biological activity in vitro.
abstract: The relationship between the A-ring chair conformation of vitamin D compounds and their ability to bind the vitamin D receptor (VDR) has long attracted the attention of many researchers. It was established that in the crystalline complexes of hVDRmt with the natural hormone, 1alpha,25-dihydroxyvitamin D(3) (1), and its side-chain analogs the vitamins exist in beta-chair form with an equatorial orientation of 1alpha-OH. However, with all these ligands the interconversion between both A-ring forms would be possible in solution. In an attempt to verify the conformation of vitamin D compounds required for binding the VDR we prepared analog 4, characterized by the presence of an axial 1alpha-hydroxy group. Since the additional ring connecting 3beta-oxygen and C-2 prevents A-ring conformational flexibility, the synthesized vitamin 4 can exist exclusively in the alpha-chair form. The geometrical isomer 5 with a free 3beta-OH group was also obtained. The analog 5 binds very poorly to VDR, whereas the vitamin 4 is practically devoid of binding ability. Both compounds also show very low HL-60-differentiating activity. When tested in vivo in mice the analogs 4 and 5 exhibit significant calcemic responses with analog 4 showing more activity than analog 5.
authors.affiliation: Department of Chemistry, Warsaw University, Pasteura 1, 02-093 Warsaw, Poland.
authors.forename: Rafal R
authors.initials: RR
authors.lastname: Sicinski
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Glebocka
authors.forename: Lori A
authors.initials: LA
authors.lastname: Plum
authors.forename: Hector F
authors.initials: HF
authors.lastname: DeLuca
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000097:blood; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D018922:HL-60 Cells; D006801:Humans; D006900:Hydroxylation; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism
chemical_list: D018167:Receptors, Calcitriol; C083610:1,25-dihydroxy-19-norvitamin D3; D002117:Calcitriol; D002118:Calcium