Biological activities of 19-nor-1α,25-dihydroxyvitamin D3 analogs singly dehydroxylated at the C-1 or C-3 position of the A-ring

Growing interests have been focused on the development of hybrid-analogs with modifications of the A-ring and the side chain of 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3]. An exocyclic methylene group at C-10, a hydroxy group at C-1 and a hydroxy group at C-3 play a crucial role in the expression of biological activities of la,25(OH)2D3. However, relationship between the functional groups and activities has not been fully understood. We have synthesized and evaluated biological activities of several singly dehydroxylated A-ring analogs of 19-nor-1 alpha,25(OH)2D3 and 19-nor-22-oxa-1 alpha,25(OH)2D3. All of them have an extremely low binding affinity for vitamin D receptor (VDR), Some of them lack the 1 alpha-hydroxy group that is considered to be essential for VDR-mediated gene expression, have greater or equivalent potencies to la,25(OH)2D3 for inducing differentiation and cell cycle G0-G1 arrest of human promyelocytic leukemia cells as well as for the transactivation of target genes including a rat 25-hydroxyvitamin D3-24-hydroxylase gene promoter and a human osteocalcin gene promoter in transfected mammalian cells. The assessment of a ligand/NDR/Retinoid X receptor complex formation using a two-hybrid luciferase assay revealed that the liganded VDR has high potency to form a heterodimer, but this could not explain the high biological potency of the 19-nor analogs. Other reason(s) including an interaction with transcriptional cofactors should be considered to explain the mechanism of action of 19-nor analogs.