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

We synthesized 25-hydroxy-26,27-dimethylvitamin D₃, 9, and 1,25-dihydroxy-26,27-dimethylvitamin D₃,14, from chol-5-enic acid-3β-ol and tested their biological activity in vivo and in vitro. 9 was found to be a 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 0 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.