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Synthesis and Properties of 14-epi-1α,25-Dihydroxy-19-Nortachysterol and its 2-Substituted Derivatives

[ Vol. 14 , Issue. 21 ]

Author(s):

Daisuke Sawada and Atsushi Kittaka   Pages 2454 - 2459 ( 6 )

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.

Keywords:

Crystal structure, 14-Epimerization, Stille coupling, Tachysterol, Vitamin D3, Vitamin D receptor.

Affiliation:

Faculty of Pharmaceutical Sciences, Teikyo University, Kaga, Itabashi-ku, Tokyo 173-8605, Japan.

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