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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 Yusuke Watarai, Michiyasu Ishizawa, Teikichi Ikura, Flavia C.M. Zacconi, Shigeru Uno, Nobutoshi Ito, Antonio Mouriño, Hiroaki Tokiwa, Makoto Makishima, and Sachiko Yamada J. Med. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.jmedchem.5b00792 • Publication Date (Web): 27 Nov 2015 Downloaded from http://pubs.acs.org on November 29, 2015
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Journal of Medicinal Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
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Journal of Medicinal Chemistry
Synthesis, Biological Activities and X-ray Crystal Structural Analysis of 25-Hydroxy-25(or 26)-adamantyl-17-[20(22),23diynyl]-21-norvitamin D Compounds Yusuke Watarai,§ Michiyasu Ishizawa,‡ Teikichi Ikura,¶ Flavia C.M. Zacconi,† Shigeyuki Uno,‡ Nobutoshi Ito,¶ Antonio Mouriño,† Hiroaki Tokiwa,§ Makoto Makishima,‡* and Sachiko Yamada‡* §
Department of Chemistry, Faculty of Science, Rikkyo University, Toshima-ku, Tokyo 1718501, Japan
‡
Department of Biomedical Sciences, Nihon University School of Medicine, Itabashi-ku, Tokyo 173-8610, Japan ¶
Medical Research Institute, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo1138510, Japan
†
Departamento de Química Orgánica, Laboratorio de Investigación Ignacio Ribas, Universidad de Santiago de Compostela, 15782 Santiago de Compostela, Spain
ABSTRACT: Novel 19-norvitamin D analogs (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 analogs was expected to interfere with helix 12 (H12, activation function 2) of the vitamin D receptor (VDR) to modulate its activities. The analog 5b
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Journal of Medicinal Chemistry
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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 life time 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 º) with respect to the original diyne vitamin D compound 6 in VDR (
