title: New 1alpha,25-dihydroxy-19-norvitamin D3 analogs with a frozen A-ring conformation.
abstract: We have recently described the synthesis of 1alpha,25-dihydroxy-19-norvitamin D3 analogs 2 and 3, possessing an additional ring connecting their 3beta-oxygen and C-2. Such structural constrains prevent the A-ring conformational flexibility and the analogs exist exclusively in the alpha-chair form with their 1alpha-hydroxy groups fixed in the axial position. The analogs bind very poorly to vitamin D receptor and are devoid of transcriptional activity. Rather unexpectedly, when tested in vivo in rats, they exhibited calcemic response significantly delayed compared to 1alpha,25-dihydroxyvitamin D3 (1). Such a response might be due to the metabolic conversion (ether cleavage?) of these compounds in the living organisms. It was therefore of interest to obtain and evaluate biologically the analogous compounds having an additional ring of purely hydrocarbon nature. Such analog 4 of 1alpha,25-dihydroxy-19-norvitamin D3, characterized by the presence of an equatorial 1alpha-hydroxy group (beta-chair form), has been synthesized by us and tested biologically. The geometrical isomer 5 having a fixed 3beta-hydroxy group was also obtained. These compounds were formed in the Julia coupling of the sulfone derived from the Grundmann ketone, and the A-ring fragment prepared in the multi-step synthesis from the (-)-quinic acid. Contrary to its counterpart 5, the analog 4 retained some affinity to vitamin D receptor.
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Glebocka
authors.forename: Rafal R
authors.initials: RR
authors.lastname: Sicinski
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* / Q000737:chemistry / Q000494:pharmacology; D002454:Cell Differentiation; D002625:Chemistry, Organic / Q000379:methods; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D018922:HL-60 Cells; D006801:Humans; D007659:Ketones / Q000737:chemistry; D007700:Kinetics; D008968:Molecular Conformation; D051381:Rats; D018167:Receptors, Calcitriol / Q000737:chemistry; D011994:Recombinant Proteins / Q000737:chemistry
chemical_list: D007659:Ketones; D018167:Receptors, Calcitriol; D011994:Recombinant Proteins; C083610:1,25-dihydroxy-19-norvitamin D3; D002117:Calcitriol