The synthesis and biological activity of 22-fluorovitamin D3: a new vitamin D analog.
We synthesized 22-fluorovitamin D3 from (22S) cholest-5-ene-3 beta, 22-diol-3 beta-acetate 2. Compound 2 was treated with diethylaminosulfur trifluoride to give 22-fluorocholest-5-en-3 beta-acetate 3 and (E) 22-dehydrocholest-5-en-3 beta-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-5 alpha,8 alpha-(3,5-dioxo-4-phenyl-1, 2,4-triazolino)-cholest-6-en-3 beta-acetate 4 was purified by flash chromatography and treated with lithium aluminum hydride to generate 22-fluorocholesta-5,7-dien-3 beta-ol 5. Photolysis of the diene 5, followed by thermal equilibration, resulted in the synthesis of 22-fluorovitamin D3 7. The vitamin 7 increased active intestinal calcium transport only at a dose of 50,000 pmol/rat, whereas vitamin D3 increased intestinal calcium transport at a dose of between 50 and 500 pmol/rat. 22-Fluorovitamin D3 7 did not mobilize bone and soft tissue calcium at a dose as high as 50,000 pmol/rat, whereas vitamin D3 was successful in doing so at a dose of 500 pmol/rat. When tested in the duodenal organ culture system, 22-fluorovitamin D3 7 had approximately 1/25th the potency of vitamin D3. It did not antagonize the activity of 1,25-dihydroxyvitamin D3. 22-Fluorovitamin D3 7 bound to the rat plasma vitamin D binding protein less avidly than vitamin D3. 22-Fluorovitamin D3 was bound very poorly to the chick intestinal cytosol receptor for 1,25-dihydroxyvitamin D3. 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 D3. 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 D3.
Gill
H S
HS
Department of Medicine, Mayo Clinic, Rochester, Minnesota 55905.
Londowski
J M
JM
Corradino
R A
RA
Kumar
R
R
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002762:Cholecalciferol / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology / Q000031:analogs & derivatives; D066298:In Vitro Techniques; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008297:Male; D051381:Rats; D013329:Structure-Activity Relationship; D014809:Vitamin D-Binding Protein / Q000378:metabolism
D014809:Vitamin D-Binding Protein; C053255:22-fluorovitamin D3; D002762:Cholecalciferol; D002118:Calcium