title: The synthesis and biological activity of 25-hydroxy-26,27-dimethylvitamin D3 and 1,25-dihydroxy-26,27-dimethylvitamin D3: highly potent novel analogs of vitamin D3.
abstract: We synthesized 25-hydroxy-26,27-dimethylvitamin D3, 9, and 1,25-dihydroxy-26,27-dimethylvitamin D3, 14, from chol-5-enic acid-3 beta-ol and tested their biological activity in vivo and in vitro. 9 was found to be highly potent vitamin D analog with bioactivity similar to that of 25-hydroxyvitamin D3. 9 bound to rat plasma vitamin D binding protein with approximately one-third the affinity of 25-hydroxyvitamin D3. In a duodenal organ culture system and in a competitive binding assay with chick intestinal 1,25-dihydroxyvitamin D receptor, 9 was significantly more potent than 25-hydroxyvitamin D3. 1,25-Dihydroxy-26,27-dimethylvitamin D3, 14 was also highly active in vivo. At doses of 1000-5000 pmol/rat, its action was more sustained than that of 1,25-dihydroxyvitamin D3. 14 bound to vitamin D binding protein about 18 times less effectively than 1,25-dihydroxyvitamin D3. 14 bound to the chick intestinal cytosol receptor with an affinity one-half that of 1,25-dihydroxyvitamin D3. In a duodenal organ culture system, 14 was about half as active as 1,25-dihydroxyvitamin D3. Extension of the sterol side chain, at C-26 and C-27, by methylene groups, prolongs the bioactivity of a vitamin D sterol hydroxylated at C-1 and C-25; the corresponding sterol, hydroxylated only at C-25, does not show any alteration of its bioactivity in vivo. These newly synthesized analogs may potentially be of therapeutic use in various mineral disorders.
authors.affiliation: Department of Medicine, Mayo Clinic, Rochester, MN 55905.
authors.forename: H S
authors.initials: HS
authors.lastname: Gill
authors.forename: J M
authors.initials: JM
authors.lastname: Londowski
authors.forename: R A
authors.initials: RA
authors.lastname: Corradino
authors.forename: A R
authors.initials: AR
authors.lastname: Zinsmeister
authors.forename: R
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001692:Biological Transport / Q000187:drug effects; D001842:Bone and Bones / Q000187:drug effects / Q000378:metabolism; D002112:Calcifediol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D002117:Calcitriol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D002118:Calcium / Q000097:blood / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D004305:Dose-Response Relationship, Drug; D007700:Kinetics; D008297:Male; D009392:Nephrectomy; D051381:Rats; D014807:Vitamin D / Q000031:analogs & derivatives*; D014808:Vitamin D Deficiency / Q000378:metabolism; D014809:Vitamin D-Binding Protein / Q000378:metabolism
chemical_list: D014809:Vitamin D-Binding Protein; C056746:25-hydroxy-26,27-dimethylvitamin D3; D014807:Vitamin D; C046127:1,25-dihydroxy-26,27-dimethylcholecalciferol; D002117:Calcitriol; D002112:Calcifediol; D002118:Calcium