Singly Dehydroxylated A-Ring Analogues of 19-Nor-1α, 25-dihydroxyvitamin D_3 and 19-Nor-22-oxa-1α, 25-dihydroxyvitamin D_3 : Novel Vitamin D_3 Analogues with Potent Transcriptional Activity but Extremely Low Affinity for Vitamin D Receptor

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1α, 25-Dihydroxsyvitamin D_3 [1α, 25(OH)_2D_3] mediates its biological activities through specific binding to the nuclear vitamin D receptor (VDR). The VDR, bound to 1α, 25(OH)_2D_3,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)_2D_3 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 D_3 and 19-nor-22-oxa-1α, 25-dihydroxyvitamin D_3,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)_2D_3 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 D_3 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)_2D_3 and the development of new 19-nor-analogues of 1α, 25(OH)_2D_3.
社団法人日本薬学会の論文
1998-12-15

Singly Dehydroxylated A-Ring Analogues of 19-Nor-1α, 25-dihydroxyvitamin D_3 and 19-Nor-22-oxa-1α, 25-dihydroxyvitamin D_3 : Novel Vitamin D_3 Analogues with Potent Transcriptional Activity but Extremely Low Affinity for Vitamin D Receptor

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