Synthesis of a 1α-C-methyl analogue of 25-hydroxyvitamin D3: interaction with a mutant vitamin D receptor Arg274Leu

Shinobu Honzawa, Naoyuki Takahashi, Atsushi Yamashita, Takayuki Sugiura, Masaaki Kurihara, Midori A. Arai, Shigeaki Kato, Atsushi Kittaka

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Vitamin D3 analogues have been developed for a mutant vitamin D receptor (VDR), Arg274Leu. The mutant VDR has a mutation at Arg274, which forms an important hydrogen bond with 1α-OH of 1α,25-dihydroxyvitamin D3 to anchor the ligand tightly in the VDR ligand binding pocket. Stereoselective synthesis of the A-ring part of the novel vitamin D analogue, 2α-(3-hydroxypropyl)-1α-methyl-25-hydroxyvitamin D3 (4), from d-galactose was accomplished with the key steps of the introduction of the methyl and allyl groups to the chiral building blocks. The new analogue 4 is ca. 7.3-fold more active than the natural hormone 1α,25-dihydroxyvitamin D3 (1).

Original languageEnglish
Pages (from-to)7135-7145
Number of pages11
JournalTetrahedron
Volume65
Issue number34
DOIs
Publication statusPublished - 2009 Aug 22
Externally publishedYes

Keywords

  • Mutant vitamin D receptor
  • Structure-function relationships
  • Vitamin D analogue
  • Vitamin D receptor

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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    Honzawa, S., Takahashi, N., Yamashita, A., Sugiura, T., Kurihara, M., Arai, M. A., Kato, S., & Kittaka, A. (2009). Synthesis of a 1α-C-methyl analogue of 25-hydroxyvitamin D3: interaction with a mutant vitamin D receptor Arg274Leu. Tetrahedron, 65(34), 7135-7145. https://doi.org/10.1016/j.tet.2009.06.029