Biological Activity Profiles of 1[alpha], 25-Dihydroxyvitamin D2, D3, D4, D7, and 24-Epi-1[alpha], 25-dihydroxyvitamin D2

We have synthesized several 1α, 25-dihydroxyvitamin D [1α, 25(OH)2D] derivatives and evaluated their biological activity in terms of their binding affinity for the vitamin D receptor (VDR) and vitamin D-binding protein(DBP), antiproliferative ro differentiation-inducing effects on human promyelocytic leukemic HL-60 cells, and transcriptional activity on a rat 25-hydroxyvitamin D3-24-hydroxylase gene promoter, including two vitamin D-responsive elements (VDREs), and human osteocalcin gene promoter, including a VDRE in transfected human osteosarcoma MG-63 cells. Furthermore, human VDR- or retinoic acid X receptor α (RXRα)-mediated luciferase activities of the derivatives were also measured by a one-hybrid system in human epitheloid carcinoma, cervix HeLa cells and African green monkey kidney CV-1 cells. Binding affinity for VDR, bone-resorbing activity, antiproliferative and cell-differentiating effects, transactivation potencies on target genes and VDR- or RXRα-mediated gene regulations of 1α, 25(OH)2D2 and 1α, 25(OH)2D4 were almost comparable to the effects of 1α, 25(OH)2D3 while 24-epi-1α, 25(OH)2D2 and 1α, 25(OH)2D7 were much less active than 1α, 25(OH)2D3 in these respects. This is the first report concerning biological assessment of 1α, 25(OH)2D2, 1α, 25(OH)2D3, 1α, 25(OH)2D4, 24-epi-1α, 25(OH)2D2 and 1α, 25(OH)2D7 at the molecular level, especially with regards to the structural differences at the 24R- or 24S-methyl group and a double bond between carbons 22 and 23 in the side chain of 1α, 25(OH)2D derivatives.