Biologic activity of dihydroxylated 19‐nor‐(pre)vitamin D 3

Vitamin D 3 and its hydroxylated metabolites are normally in thermal equilibrium with their previtamin D isomers. To evaluate the biologic activity of 1α,25‐dihydroxyprevitamin D 3 , we synthesized 19‐nor analogs of 1α,25‐dihydroxy(pre)vitamin D 3 because the absence of a C 19 methylene group prevents the isomerization of these analogs. The affinity of 1α,25‐(OH) 2 D 3 ‐19‐nor‐D 3 for the intestinal vitamin D receptor and plasma vitamin D binding protein was mildly decreased [30 and 20% of the affinity of 1α,25‐(OH) 2 D 3 , respectively], but the affinity of 1α,25‐(OH) 2 ‐19‐nor‐previtamin D 3 was only 1 and 6% of that of 1α,25‐(OH) 2 D 3 for the receptor and DBP, respectively. The in vitro effects on human promyeloid leukemia (HL‐60 cell) differentiation and osteocalcin secretion by human osteosarcoma (MG‐63) cells by 1α,25‐(OH) 2 ‐19‐nor‐D 3 were nearly identical to those of 1α‐25‐(OH) 2 D 3 , whereas 19‐nor‐previtamin D 3 showed poor activity (2%). The in vivo calcemic effects of both analogs, studied in vitamin D‐deficient chicks treated for 10 consecutive days with the analogs, showed no activity of the previtamin D 3 analog and reduced calcemic effects (≤ 10%) of 1α,25‐(OH) 2 ‐19‐nor‐D 3 . We conclude that the previtamin D form of 1α,25‐(OH) 2 D 3 has lost most of its biologic activity in vitro and in vivo.