Development of 14-epi-19-Nortachysterol and Its Unprecedented Binding Configuration for the Human Vitamin D Receptor

• Published in: Journal of the American Chemical Society Vol. 133; no. 18; pp. 7215 - 7221
• Main Authors: Sawada, Daisuke, Tsukuda, Yuya, Saito, Hiroshi, Kakuda, Shinji, Takimoto-Kamimura, Midori, Ochiai, Eiji, Takenouchi, Kazuya, Kittaka, Atsushi
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.05.2011; Amer Chemical Soc
• Subjects: Chemistry; Chemistry, Multidisciplinary; Cholecalciferol - analogs & derivatives; Cholecalciferol - chemistry; Crystallography, X-Ray; Humans; Isomerism; Ligands; Molecular Structure; Physical Sciences; Protein Binding; Receptors, Calcitriol - chemistry; Science & Technology; SYSTEM; PALLADIUM-CATALYZED SYNTHESIS; ANALOGS; A-RING; BIOLOGICAL EVALUATION; CONFORMATIONAL-ANALYSIS; D-3; D CALCIFEROL; NUCLEAR RECEPTOR
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja201481j

In the study of the synthesis of 14-epi-19-norprevitamin D3, we found 14-epi-19-nortachysterol derivatives through C6,7-cis/trans isomerization. We also succeeded in their chemical synthesis and revealed their marked stability and potent VDR binding affinity. To the best of our knowledge, this is the first isolation of stable tachysterol analogues. Surprisingly, 14-epi-19-nortachysterol derivatives exhibited an unprecedented binding configurations for the ligand binding pocket in hVDR, C5,6-s-trans and C7,8-s-trans triene configurations, which were opposite the natural C7,8-ene-configuration of 1α,25(OH)2D3.