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 journalReview articlepeer-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 languageEnglish
Pages (from-to)27-29
Number of pages3
JournalJournal of Steroid Biochemistry and Molecular Biology
Volume136
Issue number1
DOIs
Publication statusPublished - Jan 1 2013
Externally publishedYes

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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