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 | |
| Publication status | Published - 2013 |
| Externally published | Yes |
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Keywords
- 14-epi-19-Nortahcysterol
- Binding affinity
- Vitamin D analogs
- Vitamin D receptor
- Vitamin D
ASJC Scopus subject areas
- Molecular Medicine
- Endocrinology, Diabetes and Metabolism
- Molecular Biology
- Cell Biology
- Endocrinology
- Clinical Biochemistry
- Biochemistry
Cite this
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, 2013, p. 27-29.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Synthesis of 14-epi-2α-hydroxypropoxy-1α,25-dihydroxy-19- nortachysterol and its hVDR binding
AU - Sawada, Daisuke
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
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
KW - 14-epi-19-Nortahcysterol
KW - Binding affinity
KW - Vitamin D analogs
KW - Vitamin D receptor
KW - Vitamin D
UR - http://www.scopus.com/inward/record.url?scp=84881142884&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84881142884&partnerID=8YFLogxK
U2 - 10.1016/j.jsbmb.2012.11.014
DO - 10.1016/j.jsbmb.2012.11.014
M3 - Article
C2 - 23246987
AN - SCOPUS:84881142884
VL - 136
SP - 27
EP - 29
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
SN - 0960-0760
IS - 1
ER -