Fluoride substitution of vitamin D analogs at C-26 and C-27: Enhancement of activity of 25-hydroxyvitamin D but not of 1,25-dihydroxyvitamin D on bone and intestine in vitro

Paula H Stern, T. Mavreas, Y. Tanaka, H. F. DeLuca, N. Ikekawa, Y. Kobayashi

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21 Scopus citations

Abstract

A series of analogs of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] with multiple fluorine substitutions in positions 26 and 27 have been tested for their activities 1) in competing with 1,25-(OH)2D3 for binding to partially purified chick intestinal cytosol, 2) in stimulating resorption of fetal rat limb bone in vitro and 3) in competing with 25-hydroxyvitamin D3 for binding sites in rat plasma. The relative potencies of 26,26,26,27,27,27-hexafluoro-25-hydroxyvitamin D3, 26,26,26-trifluoro-25-hydroxyvitamin D3, 27-nor-26,26,26-trifluoro-25-hydroxyvitamin D3 and 25-hydroxyvitamin D3 in competing for intestinal cytosolic binding were 17:11:1:1. The relative potencies of the same series of compounds on stimulating resorption of fetal rat bones was 25:21:9:1. The relative ability of these four compounds to compete for plasma binding sites was 0.3:0.3:0.4:1.0. The results indicate that multiple fluorine substitution in the vicinity of the 25-hydroxyl group can markedly enhance the direct effects of 25-hydroxyvitamin D3 on its target tissues. This is postulated to result from the electronegativity of the fluorines which increases the acidity of the 25-hydroxyl group and enhances its affinity for the receptor. In contrast to the effects seen with the 25-hydroxyvitamin D3 analogs, multiple fluorine substitution in positions 26 and 27 did not enhance the activity of 1,25-(OH)2D3 on either cytosolic binding or bone resorption. Presumably, this is because biological activity, expressed in terms of affinity for the receptor, is already optimal in the 1,25-(OH)2D3 structure. The relative activities of the 26,27-hexafluoro derivative and 1,25-(OH)2D3 in competition for the plasma binding sites was 0.4:1.0. With respect to in vitro bone resorbing and intestinal receptor binding potency, no compound exceeded 1,25-(OH)2D3.

Original languageEnglish (US)
Pages (from-to)9-13
Number of pages5
JournalJournal of Pharmacology and Experimental Therapeutics
Volume229
Issue number1
StatePublished - Aug 30 1984

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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