title: Design, synthesis, and biological evaluation of a 1alpha,25-dihydroxy-19-norvitamin D3 analogue with a frozen A-ring conformation.
abstract: To establish the conformation of vitamin D compounds responsible for biological activity, a 1alpha,25-dihydroxy-19-norvitamin D analogue 4 possessing a 1alpha-hydroxy group fixed in the axial orientation (beta-chair form) was synthesized. The starting compounds were bicyclic lactones 6, 7a, and 7b, derived from the quinic acid lactone, which were converted to the bicyclic ketone 13. Julia coupling of this compound with sulfone 15 produced the 19-norvitamin D analogue 4, possessing an additional ring connecting the 3beta-oxygen and C-2, and the isomeric 3beta-hydroxy compound 5. In vitro, both analogues 4 and 5 exhibit reduced activity compared to the natural hormone 1, but the binding, differentiation, and transcriptional activities of analogue 5 are markedly higher than that of 4 constrained in the alpha-chair conformation. Surprisingly, in vivo tests in mice showed that the analogue 4 significantly increases serum calcium at dose levels similar to 1alpha,25-(OH)2D3. These seemingly discordant results are discussed.
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA.
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; D001667:Binding, Competitive; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002118:Calcium / Q000097:blood; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D015195:Drug Design; D005260:Female; D017930:Genes, Reporter; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D009000:Monocytes / Q000166:cytology / Q000187:drug effects; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism; D013237:Stereoisomerism; D013250:Steroid Hydroxylases / Q000235:genetics; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects; D065668:Vitamin D3 24-Hydroxylase
chemical_list: D018167:Receptors, Calcitriol; C083610:1,25-dihydroxy-19-norvitamin D3; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol; D002118:Calcium