In vitro biological activities of a series of 2 beta-substituted analogues of 1 alpha,25-dihydroxyvitamin D3.
Biological activities of a series of 2beta-substituted analogues of 1alpha,25-dihydroxyvitamin D3 [1alpha,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 regulation of the hydroxyalkyl and hydroxyalkoxy 2beta-substituted analogues were almost comparable to those of 1alpha,25(OH)2D3, while the alkyl and alkenyl analogues were much less active than 1alpha,25(OH)2D3. This study investigated the biological evaluation of a series of 2beta-substituted analogues at the molecular level, with regard to the structural differences of alkyl, alkenyl, hydroxyalkyl, hydroxyalkoxy, alkoxy, hydroxy and chloro substituents at the 2beta-position of 1alpha,25(OH)2D3.
Tsugawa
N
N
Department of Hygienic Sciences, Kobe Pharmaceutical University, Japan.
Nakagawa
K
K
Kurobe
M
M
Ono
Y
Y
Kubodera
N
N
Ozono
K
K
Okano
T
T
D000818:Animals; D001667:Binding, Competitive; D002417:Cattle; D002455:Cell Division / Q000187:drug effects; D002762:Cholecalciferol / Q000031:analogs & derivatives* / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D018922:HL-60 Cells; D006801:Humans; D007700:Kinetics; D011485:Protein Binding; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism; D013250:Steroid Hydroxylases / Q000235:genetics; D013329:Structure-Activity Relationship; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D014809:Vitamin D-Binding Protein / Q000097:blood / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase
D018167:Receptors, Calcitriol; D014809:Vitamin D-Binding Protein; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D002762:Cholecalciferol; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase