Synthesis of 14-epi-2α-hydroxypropoxy-1α,25-dihydroxy-19-nortachysterol and its hVDR binding

• Published in: The Journal of steroid biochemistry and molecular biology Vol. 136; pp. 27 - 29
• Main Authors: Sawada, Daisuke, Tsukuda, Yuya, Saito, Hiroshi, Takagi, Kenichiro, Kakuda, Shinji, Takimoto-Kamimura, Midori, Ochiai, Eiji, Takenouchi, Kazuya, Kittaka, Atsushi
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.07.2013
• Subjects: 14-epi-19-Nortahcysterol; Binding affinity; Binding Sites; Chemistry Techniques, Synthetic; Cholecalciferol - analogs & derivatives; Cholecalciferol - chemical synthesis; Cholecalciferol - metabolism; Drug Evaluation, Preclinical; Humans; Receptors, Calcitriol - chemistry; Receptors, Calcitriol - metabolism; Structure-Activity Relationship; Vitamin D analogs; Vitamin D receptor; Vitamin D3; Vitamin D analogs; Vitamin D3; 14-epi-19-Nortahcysterol; Binding affinity; Vitamin D receptor
• ISSN: 0960-0760; 1879-1220
• DOI: 10.1016/j.jsbmb.2012.11.014

▸ We synthesized a new stable 14-epi-19-nortachysterol derivative. ▸ We tested hVDR binding affinity of the 2α-substituted analog. ▸ The 2α-(3-hydroxypropoxy) group showed negative effects on the binding affinity for the hVDR. Recently, we evaluated a novel skeleton in the vitamin D family, 14-epi-1α,25(OH)2-19-nortachysterol, and discovered its unique binding configuration in the human vitamin D receptor (VDR) with the C5,6- and C7,8-s-trans triene configuration. Because of its unprecedented form, this skeleton has a promising characteristic profile for clinical use, and also the synthesis of its derivatives should be versatile. Therefore, we synthesized the novel analog, 2α-hydroxypropoxy substituted 14-epi-1α,25(OH)2-19-nortachysterol, and evaluated its human VDR binding affinity. Although this substitution is one of the promising modification of vitamin D3 such as eldecalcitol (ED-71), it had negative effects on the binding affinity, and the compound showed lower affinity than 1α,25(OH)2D3 and its parent compound, 14-epi-1α,25(OH)2-19-nortachysterol. It was thought that the unprecedented binding configuration of this skeleton should not allow the terminal hydroxyl group of the 2α-substituent to construct effective hydrogen bond networks around the amino acid residues in the binding pocket. This article is part of a Special Issue entitled ‘Vitamin D Workshop’.