title: Synthesis, biologic activity, and protein binding characteristics of a new vitamin D analog, 22-hydroxyvitamin D3.
abstract: 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 3 beta-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 greater than 22-hydroxyvitamin D3 greater than 11 alpha-hydroxyvitamin D3 greater than 1,25-dihydroxyvitamin D3 greater than 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.
mesh_terms: D000818:Animals; D001842:Bone and Bones / Q000378:metabolism; D002112:Calcifediol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use; D002117:Calcitriol / Q000037:antagonists & inhibitors; D002118:Calcium / Q000378:metabolism; D002642:Chick Embryo; D003600:Cytosol / Q000378:metabolism; D004347:Drug Interactions; D004386:Duodenum / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006887:Hydroxycholecalciferols; D008297:Male; D051381:Rats; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid / Q000378:metabolism; D013329:Structure-Activity Relationship; D014807:Vitamin D / Q000031:analogs & derivatives / Q000378:metabolism; D014808:Vitamin D Deficiency / Q000188:drug therapy; D014809:Vitamin D-Binding Protein / Q000378:metabolism
chemical_list: D006887:Hydroxycholecalciferols; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid; D014809:Vitamin D-Binding Protein; C053469:22-hydroxycholecalciferol; D014807:Vitamin D; D002117:Calcitriol; D002112:Calcifediol; D002118:Calcium