Synthesis and biological activity of 3 beta-fluorovitamin D3: comparison of the biological activity of 3 beta-fluorovitamin D3 and 3-deoxyvitamin D3.
The alteration in the biologic activity of the vitamin D3 molecule resulting from the replacement of a hydrogen atom with a fluorine atom is a subject of fundamental interest. To investigate this problem we synthesized 3 beta-fluorovitamin D3 6 and its hydrogen analog, 3-deoxyvitamin D3 7, and tested the biologic activity of each by in vitro and in vivo methods. Contrary to previous reports which showed that 3 beta-fluorovitamin D3 was as active as vitamin D3 in vivo, we found that the fluoro-analog was less active than vitamin D3. With regard to stimulation of intestinal calcium transport and bone calcium mobilization in the D-deficient hypocalcemic rat, 3 beta-fluorovitamin D3 showed significantly greater biologic activity than its hydrogen analog, 3-deoxyvitamin D3. In the organ-cultured, embryonic chick duodenum, 3 beta-fluorovitamin D3 was approx 1/1000th as active as the native hormone, 1,25-dihydroxyvitamin D3, while 3-deoxyvitamin D3 was inactive even at microM concentrations, in the induction of the vitamin D-dependent, calcium-binding protein. With regard to in vitro activity in displacing radiolabeled 25-hydroxyvitamin D3 from vitamin D binding protein and radiolabelled 1,25-dihydroxyvitamin D3 from a chick intestinal cytosol receptor, 3 beta-fluorovitamin D3 and 3 beta-deoxyvitamin D3 both showed very poor binding efficiencies when compared with vitamin D3. Our results show that the substitution of a fluorine atom for a hydrogen atom at the C-3 position of the vitamin D3 molecule results in a fluorovitamin 6 with significantly more biological activity than its hydrogen analog, 3-deoxyvitamin D3 7.
Revelle
L K
LK
Londowski
J M
JM
Kost
S B
SB
Corradino
R A
RA
Kumar
R
R
D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002642:Chick Embryo; D002762:Cholecalciferol / Q000138:chemical synthesis* / Q000494:pharmacology; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D009924:Organ Culture Techniques; D010782:Photolysis; D064030:S100 Calcium Binding Protein G / Q000096:biosynthesis; D013056:Spectrophotometry, Ultraviolet; D013997:Time Factors
D064030:S100 Calcium Binding Protein G; D002762:Cholecalciferol; D002118:Calcium