Synthesis and biological activity of 3β-fluorovitamin D 3: Comparison of the biological activity of 3β -fluorovitamin D 3 and 3-deoxyvitamin D 3

Abstract

The alteration in the biologic activity of the vitamin D 3 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 3β -fluorovitamin D 3 6 and its hydrogen analog, 3-deoxyvitarnin D 3 7, and tested the biologic activity of each by in vitro and in vivo methods. Contrary to previous reports which showed that 3β-fluorovitamin D 3 was as active as vitamin D 3 in vivo, we found that the fluoro-analog was less active than vitamin D 3. With regard to stimulation of intestinal calcium transport and bone calcium mobilization in the D-deficient hypocalcemic rat, 3β-fluorovitamin D 3 snowed significantly greater biologic activity than its hydrogen analog, 3-deoxyvitamin D 3. In the organ-cultured, embryonic chick duodenum, 3β-fluorovitamin D 3 was approx 1 1000 th as active as the native hormone, 1,25-dihydroxyvitamin D 3, while 3-deoxyvitamin D 3 was inactive even at μ M concentrations, in the induction of the vitamin D-dependent, calcium-binding protein. With regard to in vitro activity in displacing radiolabeled 25-hydroxyvitamin D 3 from vitamin D binding protein and radiolabelled 1,25-dihydroxyvitamin D 3 from a chick intestinal cytosol receptor, 3β-fluorovitamin D 3 and 3β-deoxyvitamin D 3 both showed very poor binding efficiencies when compared with vitamin D 3. Our results show that the substitution of a fluorine atom for a hydrogen atom at the C-3 position of the vitamin D 3 molecule results in a fluorovitamin 6 with significantly more biological activity than its hydrogen analog, 3-deoxyvitamin D 3 7.