The synthesis and biological activity of 22-fluorovitamin D 3: A new vitamin D analog

Abstract

We synthesized 22-fluorovitamin D 3 from (22S) cholest-5-ene-3β, 22-diol-3β-acetate 2 . Compound 2 was treated with diethylaminosulfur trifluoride to give 22-fluorocholest-5-en-3β-acetate 3 and (E) 22-dehydrocholest-5-en-3β-acetate. Compound 3 was treated with N-bromosuccinimide to give a mixture of the respective 5,7- and 4,6-dienes. The 5,7-diene of 3 was separated from the 4,6-diene using the dienophile 4-phenyl-1,2,4-triazoline-3,5-dione. 22-Fluoro-5α, 8α-(3,5-dioxo-4-phenyl-1,2,4-triazolino)-cholest-6-en-3β-acetate 4 was purified by flash chromatography and treated with lithium aluminum hydride to generate 22-fluorocholesta-5,7-dien-3β-ol 5 . Photolysis of the diene 5 , followed by thermal equilibration, resulted in the synthesis of 22-fluorovitamin D 3 7 . The vitamin 7 increased active intestinal calcium transport only at a dose of 50,000 pmol/rat, whereas vitamin D 3 increased intestinal calcium transport at a dose of between 50 and 500 pmol/rat. 22-Fluorovitamin D 3 7 did not mobilize bone and soft tissue calcium at a dose as high as 50,000 pmol/rat, whereas vitamin D 3 was successful in doing so at a dose of 500 pmol/rat. When tested in the duodenal organ culture system, 22-fluorovitamin D 3 7 had approximately 1/25th the potency of vitamin D 3. It did not antagonize the activity of 1,25-dihydroxyvitamin D 3. 22-Fluorovitamin D 3 7 bound to the rat plasma vitamin D binding protein less avidly than vitamin D 3. 22-Fluorovitamin D 3 was bound very poorly to the chick intestinal cytosol receptor for 1,25-dihydroxyvitamin D 3. We conclude that the introduction of fluorine at the C-22 position results in a vitamin D sterol with decreased biologic activity when compared to vitamin D 3. The presence of a fluorine group at C-22 position inhibits the binding of the vitamin to rat vitamin D binding protein when compared to the binding of its hydrogen analog, vitamin D 3.