title: Design, synthesis and biological properties of seco-d-ring modified 1α,25-dihydroxyvitamin D3analogues.
abstract: As a continuation of our efforts directed to the structure-activity relationship studies of vitamin D compounds, we present in this paper the synthesis of new analogues of 1α,25-(OH)2D3characterized by numerous structural modifications, especially a cleaved D ring. Total synthesis of the CD fragment required for the construction of the target vitamins was based on the Stork approach. The structure of the key intermediate - bicyclic hydroxy lactone - was established by crystallographic and electronic circular dichroism (ECD) spectral analysis. Following the attachment of the hydroxyalkyl side chain, the formed D-seco Grundmann ketone was subjected to Wittig-Horner coupling with the corresponding A-ring phosphine oxides providing two desired D-seco analogues of 19-nor-1α,25-(OH)2D3, one without a substituent at C-2 and the other possessing a 2-exomethylene group. Both compounds were biologically tested and the latter was found to be more active in in vitro tests. Despite so many structural changes introduced in its structure, the biological activity of the 2-methylene analogue approached that of the natural hormone. The synthesized D-seco vitamins, however, proved to be inactive on bone and intestine in vivo.
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison,433 Babcock Drive, Madison, WI 53706, United States; Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
authors.forename: Marcin
authors.initials: M
authors.lastname: Szybinski
authors.affiliation: Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Sektas
authors.affiliation: Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland. Electronic address: rasici@chem.uw.edu.pl.
authors.forename: Rafal R
authors.initials: RR
authors.lastname: Sicinski
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison,433 Babcock Drive, Madison, WI 53706, United States.
authors.forename: Lori A
authors.initials: LA
authors.lastname: Plum
authors.affiliation: Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland.
authors.forename: Jadwiga
authors.initials: J
authors.lastname: Frelek
authors.affiliation: Department of Biochemistry, University of Wisconsin-Madison,433 Babcock Drive, Madison, WI 53706, United States. Electronic address: deluca@biochem.wisc.edu.
authors.forename: Hector F
authors.initials: HF
authors.lastname: DeLuca
mesh_terms: D000818:Animals; D001665:Binding Sites; D050071:Bone Density Conservation Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects; D015195:Drug Design; D005765:Gastrointestinal Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D017930:Genes, Reporter / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D017207:Rats, Sprague-Dawley; D018167:Receptors, Calcitriol / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014808:Vitamin D Deficiency / Q000188:drug therapy*; D065668:Vitamin D3 24-Hydroxylase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014886:Weaning
chemical_list: D050071:Bone Density Conservation Agents; D005765:Gastrointestinal Agents; D008024:Ligands; D018167:Receptors, Calcitriol; D011994:Recombinant Proteins; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol
keywords: 19-Norvitamin D; Cellular differentiation; D-seco vitamin D; Secosteroids; Transcriptional activity; Vitamin D analogues; Vitamin D receptor