title: Increased potency of 1,25-dihydroxyvitamin D3 on human osteoblast-like cells following structural side-chain modification.
abstract: Structural modifications of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) appear to alter its biological activity. We have investigated whether the position of the C = C bond in the side chain of fluorinated analogues can alter the spectrum of activity of 1,25(OH)2D3. For this purpose we compared the actions of 26,27-hexafluoro-1,25-dihydroxy-delta 22-vitamin D3 (1,25(OH)(2)26,27F6 delta 2D3), 26,27-hexafluoro-1,25-dihydroxy-delta 23-vitamin D3 (1,25(OH)(2)26,27F6 delta 23D3) and 1,25(OH)2D3 on human osteoblast-like cells. Both analogues and 1,25(OH)2D3 stimulated the production of osteocalcin and alkaline phosphatase activity in a dose-dependent manner. Both analogues were markedly more potent than 1,25(OH)2D3 in these respects. At high concentrations the vitamin D3 analogues and metabolite inhibited DNA synthesis in a dose-dependent manner. A correlation between the inhibition of cell growth and expression of the two osteoblast markers was observed, and apart from a difference in potency, did not differ from 1,25(OH)2D3. These studies indicate that hexafluorination and the C = C bond increase the potency of 1,25(OH)2D3 on human bone-derived osteoblast-like cells in vitro, but without changing their relative activity on these various aspects of osteoblastic function tested.
authors.affiliation: Department of Human Metabolism and Clinical Biochemistry, University of Sheffield Medical School, UK.
authors.forename: D B
authors.initials: DB
authors.lastname: Evans
authors.forename: M
authors.initials: M
authors.lastname: Thavarajah
authors.forename: M R
authors.initials: MR
authors.lastname: Uskokovic
authors.forename: J A
authors.initials: JA
authors.lastname: Kanis
mesh_terms: D000135:Acid Phosphatase / Q000378:metabolism; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D002117:Calcitriol / Q000032:analysis / Q000737:chemistry / Q000494:pharmacology*; D002478:Cells, Cultured; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015394:Molecular Structure; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000502:physiology; D015675:Osteocalcin / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism
chemical_list: D011453:Prostaglandins; D015675:Osteocalcin; D004247:DNA; D000135:Acid Phosphatase; D002117:Calcitriol