文章基本信息

标题：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
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作者：Toshio OKANO ; Kimie NAKAGAWA ; Naoko TSUGAWA 等
期刊名称：Biological and Pharmaceutical Bulletin
印刷版ISSN：0918-6158
电子版ISSN：1347-5215
出版年度：1998
卷号：21
期号：12
页码：1300-1305
DOI：10.1248/bpb.21.1300
出版社：The Pharmaceutical Society of Japan
摘要：1α, 25-Dihydroxsyvitamin D₃ [1α, 25(OH)₂D₃] mediates its biological activities through specific binding to the nuclear vitamin D receptor (VDR). The VDR, bound to 1α, 25(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.
关键词：19-nor-1α, 25-dihydroxyvitamin D3 analogue;19-nor-22-oxa-1α, 25-dihydroxyvitamin D3 analogue;anti-proliferation;cell-differentiation;transactivation