title: D-seco-Vitamin D analogs having reversed configurations at C-13 and C-14: Synthesis, docking studies and biological evaluation.
abstract: Prompted by results of molecular modeling performed on the seco-d-ring-vitamins D, we turned our attention to such analogs, having reversed configurations at C-13 and C-14, as the next goals of our studies on the structure-activity relationship for vitamin D compounds. First, we developed an efficient total synthesis of the "upper" C/seco-d-ring fragment with a 7-carbon side chain. Then, we coupled it with A-ring fragments using Sonogashira or Wittig-Horner protocol, providing the targeted D-seco analogs of 1α,25-dihydroxyvitamin D3and 1α,25-dihydroxy-19-norvitamin D3possessing a vinyl substituent at C-14 and a double bond between C-17 and C-20. The affinities of the synthesized vitamin D analogs to the full-length recombinant rat VDR were examined, as well as their differentiating and transcriptional activities. In these in vitro tests, they were significantly less active compared to 1α,25-(OH)2D3. Moreover, it was established that the analogs tested in vivo in rats showed no calcemic potency.
authors: Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA; Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
authors: Marcin
authors: M
authors: Szybinski
authors: Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland.
authors: Katarzyna
authors: K
authors: Sokolowska
authors: Department of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland. Electronic address: rasici@chem.uw.edu.pl.
authors: Rafal R
authors: RR
authors: Sicinski
authors: Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA.
authors: Lori A
authors: LA
authors: Plum
authors: Department of Biochemistry, University of Wisconsin-Madison, 433 Babcock Drive, Madison, WI 53706, USA.
authors: Hector F
authors: HF
authors: DeLuca
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D060326:Chemistry Techniques, Synthetic; D006801:Humans; D062105:Molecular Docking Simulation; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism; D014808:Vitamin D Deficiency / Q000188:drug therapy / Q000378:metabolism; D014815:Vitamins / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D018167:Receptors, Calcitriol; C579457:VDR protein, human; D014815:Vitamins; D002117:Calcitriol
keywords: 2MD; Secosteroids; Sonogashira coupling; Vitamin D analogs; Vitamin D receptor