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

Abstract

Twelve new analogues of 19-nor-1α,25-dihydroxyvitamin D3 6–17, 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 analogues 14–17 with a 2β-methyl substitution had little or no activiy in vitro and in vivo as expected from previous work.

Strategies for the Synthesis of 19-nor-Vitamin D Analogs

“…They also used the attachment of two methyl groups on C22 to help elucidate the biological impact of the double substitution of this side chain carbon. With the aim to test the influence of removing one [58] or both [59] methyl groups located at C25 on the biological in vitro and in vivo activity, DeLuca's research group prepared 24 new analogs of 19-nor-1α,25-dihydroxyvitamin D 3 (152-155, Scheme 29). To produce these compounds, a convergent approach via a Wittig-Horner reaction between Grundmann's ketone derivatives 151, either possessing fixed configurations of the hydroxyl group at C25 (X = OH) or lacking it (X = H), and the A-ring synthon 34a.…”