Effect of substituting fluorine for hydrogen at C-26 and C-27 on the side chain of 1,25-dihydroxyvitamin D3.

Abstract Previous reports have demonstrated that introduction of fluorine atoms at C-26 and C-27 of 1,25-dihydroxyvitamin D 3 (1,25-(OH) 2 D 3 ) results in the potentiation of various aspects of some biological activities. The higher biological activities of 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D 3 (26,27-F 6 -1,25-(OH) 2 D 3 ) were accounted for in part by a decrease in metabolic inactivation via the 26-and 27-hydroxylation pathways. In addition to 26,27-F 6 -1,25-(OH) 2 D 3 not being hydroxylated in the 26 and 27 positions, it did not undergo 24-hydroxylation despite a significant induction by 26,27-F 6 -1,25-(OH) 2 D 3 of 24-hydroxylase activity in the HL-60 cell system. Another fluorinated vitamin D 3 analog, 26,26,26,27,27,27-hexafluoro-1α-hydroxyvitamin D 3 (26,27-F 6 -1α-OH-D 3 ) may not undergo 25-hydroxylation as efficiently as 1α-OH-D 3 in vivo because a rise in serum 26,27-F 6 -1,25-(OH) 2 D 3 levels after injection of 26,27-F 6 -1α-OH-D 3 was delayed significantly with a much smaller amplitude. Furthermore, 26,26,26,27,27,27-hexafluoro-1,23( S ),25-trihydroxyvitamin D 3 retained full activity in the induction of HL-60 cell differentiation even after 23( S )-hydroxylation, in contrast to 1,23( S ),25-(OH) 3 D 3 . These data suggested that substitution of fluorines for hydrogens at C-26 and at C-27 positions may result in alteration in chemical reactivity and/or conformation of C-23, C-24 and C-25 positions of the 1,25(OH) 2 D 3 molecule.