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

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 th...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2011-05, Vol.133 (18), p.7215-7221
Main Authors: Sawada, Daisuke, Tsukuda, Yuya, Saito, Hiroshi, Kakuda, Shinji, Takimoto-Kamimura, Midori, Ochiai, Eiji, Takenouchi, Kazuya, Kittaka, Atsushi
Format: Article
Language:English
Subjects:
Cholecalciferol - analogs & derivatives
Cholecalciferol - chemistry
Crystallography, X-Ray
Humans
Isomerism
Ligands
Molecular Structure
Protein Binding
Receptors, Calcitriol - chemistry
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Summary: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.
ISSN:0002-7863
1520-5126
DOI:10.1021/ja201481j