1-FLUOROVITAMIN-D3, A VITAMIN-D3 ANALOG MORE ACTIVE ON BONE-CALCIUM MOBILIZATION THAN ON INTESTINAL-CALCIUM TRANSPORT

The chemical synthesis, spectral characterization, and biological activity of 1-fluorovitamin D3 are described. The title compound was synthesized through direct fluorination of la-hydroxyvitamin D3 3β-acetate and characterized by ultraviolet, nuclear magnetic resonance, and mass spectroscopy. Similar responses of bone-calcium mobilization in vitamin D deficient rats are given by 200-300 ng of 1-fluorovitamin D3 and 25 ng of vitamin D3. Likewise, vitamin D3 and 1-fluorovitamin D3 provide the same degree of epiphyseal plate calcification in rachitic rats at daily doses of 20 and 270 ng, respectively. Thus, there appeared to be an approximate 10-to 15-fold difference in their ability to cause calcium and phosphate mobilization. However, about 1260 ng of 1-fluorovitamin D3 is necessary to produce the same degree of intestinal-calcium transport as 12.5 ng of vitamin D3—a difference of about 100-fold. Therefore, relative to vitamin D3, 1-fluorovitamin D3 demonstrates at least partial selectivity for mediating calcium metabolism in bone as opposed to mediating calcium metabolism in intestine. 1-Fluorovitamin D3 causes maximum stimulation of bone-calcium mobilization and intestinal-calcium transport 24 h after a single, intravenous dose, like vitamin D3 but in contrast to la-hydroxyvitamin D3 which shows maximum responses at about 12 h. Neph-rectomized animals do not respond to the fluoro analogue at doses higher than those which would cause significant responses in intact animals. Thus, 1-fluorovitamin D3 probably undergoes metabolism in the kidney prior to manifesting physiological activity. © 1979, American Chemical Society. All rights reserved.