In Vitro Biological Activities of a Series of 2β-Substituted Analogues of 1α, 25-Dihydroxyvitamin D₃

Abstract

Biological activities of a series of 2β-substituted analogues of 1α, 25-dihydroxyvitamin D₃ [1α, 25(OH)₂D₃] were evaluated in vitro in terms of their binding affinity with regard to calf thymus cytosolic vitamin D receptor (VDR) and rat plasma vitamin D-binding protein (DBP). Additionally, reporter gene luciferase activities using either a rat 25-hydroxyvitamin D₃-24-hydroxylase gene promoter, including two vitamin D-responsive elements (VDREs), in transfected rat osteoblast-like ROS17/2.8 cells, or a human VDR-GAL4 modified two-hybrid system in transfected human epitheloid carcinoma, cervix HeLa cells were examined. Binding affinity for VDR, transactivation potency on the target gene and VDR-mediated gene ergulation of the hydroxyalkyl and hydroxyalkoxy 2β-substituted analogues were almost comparable to those of 1α, 25(OH)₂D₃, while the alkyl and alkenyl analogues were much les active than 1α, 25(OH)₂D₃. This study investigated the biological evaluation of a series of 2β-substituted analogues at the molecular level, with regard to the structural differences of alkyl, alkenyl, hydroxyalkyl, hydroxyalkoxy, alkoxy, hydroxy and chloro substituents at the 2β-position of 1α, 25(OH)₂D₃.