Synthesis, biologic activity, and protein binding characteristics of a new vitamin D analog, 22-hydroxyvitamin D 3

Abstract

We synthesized a novel vitamin D analog, 22-hydroxyvitamin D 3 9 and tested its biologic activity (and antivitamin properties) in vivo in vitamin D-deficient rats, and in vitro in the chick embryonic duodenum. We examined its ability to bind to the sterol carrier protein, vitamin D binding protein and the chick intestinal cytosol receptor for 1,25-dihydroxyvitamin D 3. The new vitamin 9 was synthesized from 3β-hydroxy-22,23-dinorcholenic acid 1 in 12 steps. The vitamin 9 displayed no vitamin D agonist activity in the intestine or in bone in vivo and did not block the activity of vitamin D 3 or 25-hydroxyvitamin D 3. It was a weak vitamin D 3 agonist in the chick embryonal duodenum in vitro. It did not antagonize the activity of 1,25-dihydroxyvitamin D 3. Vitamin 9 bound to the chick intestinal cytosol receptor with low affinity. 22-Hydroxyvitamin D 3 and various vitamin D sterols were bound to vitamin D binding protein in the following order: 25-hydroxyvitamin D 3, (24R)-24,25-dihydroxyvitamin D 3, and (25S)-25,26-dihydroxyvitamin D 3 >22-hydroxyvitamin D 3 >11α -hydroxyvitamin D 3 >1,25-dihydroxy-vitamin D 3 >vitamin D 3. We conclude that the introduction of a hydroxyl group at C-22 in the side chain of the vitamin D 3 molecule decreases its biological activity.