A環の1位または3位のいずれかの水酸基を欠失した19-Nor-1α, 25-dihydroxyvitamin D_3誘導体の生物活性

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Recently, growing interests have been focused on the development of hybrid-analogues with modifications of the A-ring and the side chain of 1α,25-dihydroxyvitamin D_3[1α,25(OH)_2D_3]. 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. However, relationship between the functional groups and activities has not been fully understood. We have synthesized and evaluated biological activities of several singly dehydoxylated A-ring analogues of 19-nor-1α,25(OH)_2D_3 and 19-nor-22-oxa-1α,25(OH)_2D_3. All of them have an extremely low binding affinity for vitamin D receptor (VDR). Some of them lack the lrt-hydroxy group that is considered to be essential for VDR-mediated gene expres sion, have greater or equivalent potencies to 1α,25(OH)_2D_3 for inducing differentiation and cell cycle G_0-G_1 arrest of HL-60 cells as well as for the transactivation of target genes including a rat 25(OH)D_3 24-hydroxylase gene promoter and a human osteocalcin gene promoter in transfected mammalian cells. The assessment of a ligand/VDR/Retinoid X receptor (RXR) 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 analogues. Other reason(s) including an interaction with transcriptional cofactors should be considered to explain the mechanism of action of 19-nor analogues.
1999-11-25

A環の1位または3位のいずれかの水酸基を欠失した19-Nor-1α, 25-dihydroxyvitamin D_3誘導体の生物活性

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