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

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.