Synthesis and biological activity of the A-ring modified 1α, 25-dihydroxyvitamin D3

Hiroaki Takayama, Atsushi Kittaka, Toshie Fujishima, Yoshitomo Suhara

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

We have systematically synthesized 2α-functionalized 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] 1 based on a convergent method using Pd-catalyzed alkylative cyclization with the A-ring precursor enynes and the CD-ring bromoolefin 5 in the following three categories: 2α-alkyl, 2α-hydroxyalkyl, and 2α-hydroxyalkoxyl derivatives, in order to study the structure-activity relationships of the natural hormone 1α,25(OH)2D3, particularly on the A-ring. First, the 2-methyl analogues 2 were designed and all eight possible diastereomers on the A-ring stereochemistry at C 1, C 2, and C 3 were synthesized from the A-ring precursor enynes 22a-h, which were prepared from methyl (S)- and (R)-3-hydroxy-2-methylpropionate. Biological activities including affinities to vitamin D receptor (VDR) and vitamin D binding protein (DBP), elevation of serum Ca level, induction of HL-60 cell differentiation, and apoptosis are discussed. Next, on the basis of biological activities of the 2α-methyl derivative, the other types of 2α-functional groups were introduced stereoselectively into the 1α,25(OH)2D3 skeleton using the A-ring precursor enynes derived from D-xylose or D-glucose. Five of these synthetic 2α-modified analogues showed higher VDR binding affinity than that of the natural hormone. Docking studies of the synthetic ligands to VDR based on Moras' X-ray results and remarkably high biological activities are described.

Original languageEnglish
Pages (from-to)370-382
Number of pages13
JournalYuki Gosei Kagaku Kyokaishi/Journal of Synthetic Organic Chemistry
Volume60
Issue number4
DOIs
Publication statusPublished - 2002 Apr

Keywords

  • 2-substituted 1α
  • 25-dihydroxyvitamin D
  • A-ring conformation
  • Apoptosis
  • Calcium mobilization
  • Cell-differentiation
  • Structure-activity relationship
  • Synthesis
  • VDR binding affinity
  • VDR-ligand docking model
  • Vitamin D receptor (VDR)

ASJC Scopus subject areas

  • Organic Chemistry

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