Elsevier

Biochemical Pharmacology

Volume 45, Issue 11, 9 June 1993, Pages 2331-2336
Biochemical Pharmacology

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

https://doi.org/10.1016/0006-2952(93)90207-DGet rights and content

Abstract

Previous reports have demonstrated that introduction of fluorine atoms at C-26 and C-27 of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) 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 D3 (26,27-F6-1,25-(OH)2D3) were accounted for in part by a decrease in metabolic inactivation via the 26-and 27-hydroxylation pathways. In addition to 26,27-F6-1,25-(OH)2D3 not being hydroxylated in the 26 and 27 positions, it did not undergo 24-hydroxylation despite a significant induction by 26,27-F6-1,25-(OH) 2D3 of 24-hydroxylase activity in the HL-60 cell system. Another fluorinated vitamin D3 analog, 26,26,26,27,27,27-hexafluoro-1α-hydroxyvitamin D3 (26,27-F6-1α-OH-D3) may not undergo 25-hydroxylation as efficiently as 1α-OH-D3in vivo because a rise in serum 26,27-F6-1,25-(OH)2D3 levels after injection of 26,27-F6-1α-OH-D3 was delayed significantly with a much smaller amplitude. Furthermore, 26,26,26,27,27,27-hexafluoro-1,23(S),25-trihydroxyvitamin D3 retained full activity in the induction of HL-60 cell differentiation even after 23(S)-hydroxylation, in contrast to 1,23(S),25-(OH)3D3. 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) 2D3 molecule.

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