Increased potency of 1,25-dihydroxyvitamin D3 on human osteoblast-like cells following structural side-chain modification.

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.