2. Academic Validation
  3. Synthesis, Biological Activities, and X-ray Crystal Structural Analysis of 25-Hydroxy-25(or 26)-adamantyl-17-[20(22),23-diynyl]-21-norvitamin D Compounds

Synthesis, Biological Activities, and X-ray Crystal Structural Analysis of 25-Hydroxy-25(or 26)-adamantyl-17-[20(22),23-diynyl]-21-norvitamin D Compounds

  • J Med Chem. 2015 Dec 24;58(24):9510-21. doi: 10.1021/acs.jmedchem.5b00792.
Yusuke Watarai 1,  Michiyasu Ishizawa 2,  Teikichi Ikura 3,  Flavia C M Zacconi 4,  Shigeyuki Uno 2,  Nobutoshi Ito 3,  Antonio Mouriño 4,  Hiroaki Tokiwa 1,  Makoto Makishima 2,  Sachiko Yamada 2
Affiliations

Affiliations

  • 1 Department of Chemistry, Faculty of Science, Rikkyo University , Toshima-ku, Tokyo 171-8501, Japan.
  • 2 Department of Biomedical Sciences, Nihon University School of Medicine , 30-1 Ohyaguchikami-machi, Itabashi-ku, Tokyo 173-8610, Japan.
  • 3 Medical Research Institute, Tokyo Medical and Dental University , Bunkyo-ku, Tokyo 113-8510, Japan.
  • 4 Departamento de Química Orgánica, Laboratorio de Investigación Ignacio Ribas, Universidad de Santiago de Compostela , 15782 Santiago de Compostela, Spain.
PMID: 26613420 DOI: 10.1021/acs.jmedchem.5b00792
Abstract

Novel 19-norvitamin D analogues (ADYW1-4, 5a-d) in which an adamantyl diyne side chain is attached directly to the 17-position of the D ring are designed and stereoselectively synthesized. The adamantane ring of these analogues was expected to interfere with helix 12 (H12, activation function 2) of the vitamin D receptor (VDR) to modulate its activities. The analogue 5b binds to the VDR (7% of the natural hormone) and shows significant partial agonistic activity in transactivation assay. Compound 5b showed considerable selectivity in VDR target genes expressions in vitro, it was taken up by target cells 2-3 times more readily, and its lifetime was three times longer than the natural hormone. The X-ray crystal structure of 5b in complex with VDR reveals that the ligand binds similarly to the natural hormone, but the diyne moiety is slightly bent (angles around the diyne 5° to 8°) with respect to the original diyne vitamin D compound 6 in VDR (<1°) due to steric hindrance with helix 12.

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