title: Synthesis and biological activity of novel vitamin D analogues: 24,24-difluoro-25-hydroxy-26,27-dimethylvitamin D3 and 24,24-difluoro-1 alpha,25-dihydroxy-26,27-dimethylvitamin D3.
abstract: We synthesized 24,24-difluoro-25-hydroxy-26,27-dimethylvitamin D3 (16), and 24,24-difluoro-1 alpha, 25-dihydroxy-26,27-dimethylvitamin D3 (21), from 3 beta-hydroxy-22,23-dinorcholenic acid 3-acetate. Compound 16 was found to be a highly potent vitamin D analogue with bioactivity similar to that of 25-hydroxyvitamin D3 in vivo. Compound 16 was bound by vitamin D binding protein with an affinity slightly less than that of 25-hydroxyvitamin D3. It was bound to the intestinal cytosol receptor for 1,25-dihydroxyvitamin D3 with approximately the same affinity as that of 25-hydroxyvitamin D3. In the organ-culture duodenum, 16 induced the synthesis of calcium binding protein with a potency approximately 1/20 that of 1,25-dihydroxyvitamin D3. Compound 21 was also noted to be a highly potent vitamin D analogue with bioactivity in vivo similar to that of 1,25-dihydroxyvitamin D3. It was bound to vitamin D binding protein with an affinity considerably less than that of 1,25-dihydroxyvitamin D3. It was bound to the intestinal cytosol receptor for 1,25-dihydroxyvitamin D3 with an affinity slightly less than that of the native hormone. In the organ-culture duodenum, 21 was noted to be about 3 times more active than 1,25-dihydroxyvitamin D3 in the induction of calcium binding protein. The introduction of fluorines at C-24 and extension of the sterol side chain at C-26 and C-27 by methylene groups results in vitamin D analogues that have biological activity in vivo similar to those of the respective nonfluorinated natural sterols.
authors: Department of Medicine, Mayo Clinic and Foundation, Rochester, Minnesota 55905.
authors: H S
authors: HS
authors: Gill
authors: J M
authors: JM
authors: Londowski
authors: R A
authors: RA
authors: Corradino
authors: A R
authors: AR
authors: Zinsmeister
authors: R
authors: R
authors: Kumar
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001692:Biological Transport; D001842:Bone and Bones / Q000378:metabolism; D002112:Calcifediol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D002118:Calcium / Q000097:blood / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051381:Rats; D018167:Receptors, Calcitriol; D011987:Receptors, Steroid / Q000378:metabolism; D013329:Structure-Activity Relationship; D014809:Vitamin D-Binding Protein / Q000378:metabolism
chemical_list: D018167:Receptors, Calcitriol; D011987:Receptors, Steroid; D014809:Vitamin D-Binding Protein; C062807:24,24-difluoro-25-hydroxy-26,27-dimethylvitamin D3; C062808:24,24-difluoro-1,25-dihydroxy-26,27-dimethylvitamin D3; D002117:Calcitriol; D002112:Calcifediol; D002118:Calcium