26- and 27-Methyl groups of 2-substituted, 19-nor-1α,25-dihydroxylated vitamin D compounds are essential for calcium mobilization in vivo

Twelve new analogs of 19-nor-1α,25-dihydroxyvitamin D36–17, were prepared by a multi-step procedure from known alcohols 18 and 19. We have examined the influence of removing two methyl groups located at C-25, as well as the 25-hydroxy group, on the biological in vitro and in vivo biological activity. Surprisingly, removal of the 26- and 27-methyl groups from either the 2α-methyl or 2-methylene-19-nor-1α,25-dihydroxyvitamin D3 reduced vitamin D receptor binding, HL-60 differentiation, and 25-hydroxylase transcription in vitro only slightly to moderately (compounds 6–13). However, these compounds were devoid of in vivo bone mobilization activity and had markedly reduced activity on intestinal calcium transport. The analogs 14–17 with a 2β-methyl substitution had little or no activity in vitro and in vivo as expected from previous work.

Graphical abstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► 26- and 27-Methyl groups of 19-nor-1,25(OH)2D required for Ca mobilization in vivo. ► A β-methyl on C-2 of 19-nor-1,25-(OH)2D eliminates in vitro and in vivo activity. ► 26,27-Methyls of 19-nor-1,25(OH)2D3 are not required for intestinal Ca transport.