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

Daisuke Sawada; Yuya Tsukuda; Hiroshi Saito; Kenichiro Takagi; Shinji Kakuda; Midori Takimoto-Kamimura; Eiji Ochiai; Kazuya Takenouchi; Atsushi Kittaka

doi:10.1016/j.jsbmb.2012.11.014

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

Daisuke Sawada, Yuya Tsukuda, Hiroshi Saito, Kenichiro Takagi, Shinji Kakuda, Midori Takimoto-Kamimura, Eiji Ochiai, Kazuya Takenouchi, Atsushi Kittaka

Research output: Contribution to journal › Review article › peer-review

6 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	27-29
Number of pages	3
Journal	Journal of Steroid Biochemistry and Molecular Biology
Volume	136
Issue number	1
DOIs	https://doi.org/10.1016/j.jsbmb.2012.11.014
Publication status	Published - Jan 1 2013
Externally published	Yes

Keywords

14-epi-19-Nortahcysterol
Binding affinity
Vitamin D analogs
Vitamin D receptor

ASJC Scopus subject areas

Endocrinology, Diabetes and Metabolism
Biochemistry
Molecular Medicine
Molecular Biology
Endocrinology
Clinical Biochemistry
Cell Biology

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Synthesis of 14-epi-2α-hydroxypropoxy-1α,25-dihydroxy-19- nortachysterol and its hVDR binding. / Sawada, Daisuke; Tsukuda, Yuya; Saito, Hiroshi; Takagi, Kenichiro; Kakuda, Shinji; Takimoto-Kamimura, Midori; Ochiai, Eiji; Takenouchi, Kazuya; Kittaka, Atsushi.

In: Journal of Steroid Biochemistry and Molecular Biology, Vol. 136, No. 1, 01.01.2013, p. 27-29.

Research output: Contribution to journal › Review article › peer-review

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abstract = "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.",

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author = "Daisuke Sawada and Yuya Tsukuda and Hiroshi Saito and Kenichiro Takagi and Shinji Kakuda and Midori Takimoto-Kamimura and Eiji Ochiai and Kazuya Takenouchi and Atsushi Kittaka",

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AU - Tsukuda, Yuya

AU - Saito, Hiroshi

AU - Takagi, Kenichiro

AU - Kakuda, Shinji

AU - Takimoto-Kamimura, Midori

AU - Ochiai, Eiji

AU - Takenouchi, Kazuya

AU - Kittaka, Atsushi

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