Synthesis, biologic activity, and protein binding characteristics of a new vitamin D analog, 22-hydroxyvitamin D₃

We synthesized a novel vitamin D analog, 22-hydroxyvitamin D₃ 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 D₃. 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 D₃ or 25-hydroxyvitamin D₃. It was a weak vitamin D₃ agonist in the chick embryonal duodenum in vitro. It did not antagonize the activity of 1,25-dihydroxyvitamin D₃. Vitamin 9 bound to the chick intestinal cytosol receptor with low affinity. 22-Hydroxyvitamin D₃ and various vitamin D sterols were bound to vitamin D binding protein in the following order: 25-hydroxyvitamin D₃, (24R)-24,25-dihydroxyvitamin D₃, and (25S)-25,26-dihydroxyvitamin D₃ >22-hydroxyvitamin D₃ >11α -hydroxyvitamin D₃ >1,25-dihydroxy-vitamin D₃ >vitamin D₃. We conclude that the introduction of a hydroxyl group at C-22 in the side chain of the vitamin D₃ molecule decreases its biological activity.