Singly dehydroxylated A-ring analogues of 19-nor-1α,25- dihydroxyvitamin D3 and 19-nor-22-oxa-1α,25-dihydroxyvitamin D3: Novel vitamin D3 analogues with potent transcriptional activity but extremely low affinity for vitamin D receptor

Toshio Okano, Kimie Nakagawa, Naoko Tsugawa, Keiichi Ozono, Noboru Kubodera, Ayako Osawa, Masahiro Terada, Koichi Mikami

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)


1α,25-Dihydroxyvitamin D3 [1α,25(OH)2D3] mediates its biological activities through specific binding to the nuclear vitamin D receptor (VDR). The VDR, bound to 1α25(OH)2D3, forms a heterodimer with a nuclear accessory factor, retinoid X receptor (RXR), and the complex subsequently binds to specific nucleotide sequences or a vitamin D-responsive element (VDRE) to induce gene transcriptions. Thus, an ideal analogue of 1α,25(OH)2D3 for therapeutic applications has been considered to be one which has a high binding affinity for VDR, thus forming a stable VDR/RXR complex, and binding strongly to VDRE. By contrast, we report here evidence contrary to this hypothesis. Several singly dehydroxylated A-ring analogues of 19-nor-1α,25-dihydroxyvitamin D3 and 19-nor-22-oxa-1α,25- dihydroxyvitamin D3, all of which have an extremely low binding affinity for VDR, and some of which lack the 1α-hydroxyl group that is considered to be essential for VDR-mediated gene expression, have greater or equivalent potencies to 1α,25(OH)2D3 for inhibiting the proliferation and inducing the differentiation of HL-60 cells, as well as inducing the transactivation of a luciferase reporter gene combining a rat 25-hydroxyvitamin D3 24- hydroxylase gene promoter containing two VDREs. The present findings open interesting possibilities as to the role of the VDR in the genomic action of 1α,25(OH)2D3 and the development of new 19-nor-analogues of 1α,25(OH)2D3.

Original languageEnglish
Pages (from-to)1300-1305
Number of pages6
JournalBiological and Pharmaceutical Bulletin
Issue number12
Publication statusPublished - 1998
Externally publishedYes


  • 19-nor-1α,25-dihydroxyvitamin D analogue
  • 19-nor-22-oxa-1α,25- dihydroxyvitamin D analogue
  • Anti-proliferation
  • Cell- differentiation
  • Transactivation

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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