Synthesis and properties of 14-epi-1α,25-dihydroxy-19-nortachysterol and its 2-substituted derivatives

Daisuke Sawada; Atsushi Kittaka

doi:10.2174/1568026615666141208103741

Synthesis and properties of 14-epi-1α,25-dihydroxy-19-nortachysterol and its 2-substituted derivatives

Daisuke Sawada, Atsushi Kittaka

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

Abstract

As the first stable tachysterol analogs, 14-epi-19-nortachysterol and its 2-substituted derivatives were synthesized using the Stille coupling reaction between the A-ring precursor (three vinylstannanes) and the CD-ring vinyl trifrate. Among them, the 2-methylidene group was hydrogenated with Wilkinson’s catalyst regioselectively to obtain 2α- and 2β-methyl analogs after separation; therefore, five new 14-epi-19-nortachysterols were constructed. All 14-epi-19-nortachysterols showed moderate to strong human vitamin D receptor (hVDR) binding affinity except the 2α-(3-hydroxypropoxy) substituted analog. X-ray cocrystallographic analysis of the [truncated hVDR]-[2-methyl-14-epi-19-nortachysterol] complex exhibited an unusual binding structure that has not been observed previously.

Original language	English
Pages (from-to)	2454-2459
Number of pages	6
Journal	Current Topics in Medicinal Chemistry
Volume	14
Issue number	21
DOIs	https://doi.org/10.2174/1568026615666141208103741
Publication status	Published - Jan 1 2014

Keywords

14-Epimerization
Crystal structure
Stille coupling
Tachysterol
Vitamin D
Vitamin D receptor

ASJC Scopus subject areas

Drug Discovery

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title = "Synthesis and properties of 14-epi-1α,25-dihydroxy-19-nortachysterol and its 2-substituted derivatives",

abstract = "As the first stable tachysterol analogs, 14-epi-19-nortachysterol and its 2-substituted derivatives were synthesized using the Stille coupling reaction between the A-ring precursor (three vinylstannanes) and the CD-ring vinyl trifrate. Among them, the 2-methylidene group was hydrogenated with Wilkinson{\textquoteright}s catalyst regioselectively to obtain 2α- and 2β-methyl analogs after separation; therefore, five new 14-epi-19-nortachysterols were constructed. All 14-epi-19-nortachysterols showed moderate to strong human vitamin D receptor (hVDR) binding affinity except the 2α-(3-hydroxypropoxy) substituted analog. X-ray cocrystallographic analysis of the [truncated hVDR]-[2-methyl-14-epi-19-nortachysterol] complex exhibited an unusual binding structure that has not been observed previously.",

keywords = "14-Epimerization, Crystal structure, Stille coupling, Tachysterol, Vitamin D, Vitamin D receptor",

author = "Daisuke Sawada and Atsushi Kittaka",

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T1 - Synthesis and properties of 14-epi-1α,25-dihydroxy-19-nortachysterol and its 2-substituted derivatives

AU - Sawada, Daisuke

AU - Kittaka, Atsushi

PY - 2014/1/1

Y1 - 2014/1/1

N2 - As the first stable tachysterol analogs, 14-epi-19-nortachysterol and its 2-substituted derivatives were synthesized using the Stille coupling reaction between the A-ring precursor (three vinylstannanes) and the CD-ring vinyl trifrate. Among them, the 2-methylidene group was hydrogenated with Wilkinson’s catalyst regioselectively to obtain 2α- and 2β-methyl analogs after separation; therefore, five new 14-epi-19-nortachysterols were constructed. All 14-epi-19-nortachysterols showed moderate to strong human vitamin D receptor (hVDR) binding affinity except the 2α-(3-hydroxypropoxy) substituted analog. X-ray cocrystallographic analysis of the [truncated hVDR]-[2-methyl-14-epi-19-nortachysterol] complex exhibited an unusual binding structure that has not been observed previously.

AB - As the first stable tachysterol analogs, 14-epi-19-nortachysterol and its 2-substituted derivatives were synthesized using the Stille coupling reaction between the A-ring precursor (three vinylstannanes) and the CD-ring vinyl trifrate. Among them, the 2-methylidene group was hydrogenated with Wilkinson’s catalyst regioselectively to obtain 2α- and 2β-methyl analogs after separation; therefore, five new 14-epi-19-nortachysterols were constructed. All 14-epi-19-nortachysterols showed moderate to strong human vitamin D receptor (hVDR) binding affinity except the 2α-(3-hydroxypropoxy) substituted analog. X-ray cocrystallographic analysis of the [truncated hVDR]-[2-methyl-14-epi-19-nortachysterol] complex exhibited an unusual binding structure that has not been observed previously.

KW - 14-Epimerization

KW - Crystal structure

KW - Stille coupling

KW - Tachysterol

KW - Vitamin D

KW - Vitamin D receptor

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Synthesis and properties of 14-epi-1α,25-dihydroxy-19-nortachysterol and its 2-substituted derivatives

Abstract

Keywords

ASJC Scopus subject areas

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