Abstract
During our ongoing structure–activity studies in the vitamin D area, we obtained (20 S)-1α,25-dihydroxy-2-methylene-19-norvitamin D 3 ( 5). This analog, designated 2MD, is characterized by a significantly enhanced calcemic activity and is currently evaluated as a potential drug for osteoporosis. Therefore, it was of interest to synthesize also its 1-desoxy analog and to evaluate its biological action. These studies were aimed at solving an intriguing problem: can such a vitamin also be hydroxylated in vivo at the allylic C-1 position despite lack of the exomethylene moiety at C-10? The Wittig-Horner coupling of the known protected (20 S)-25-hydroxy Grundmann ketone 17 and the phosphine oxides 16 and 33, differing in their hydroxyls protection, provided the target 1-desoxy-2MD ( 6) after removal of the silyl protecting groups. Two synthetic paths have been elaborated leading to the desired A-ring synthons and starting from commercially available compounds: 1,4-cyclohexanedione monoethylene acetal ( 7) and (−)-quinic acid ( 19). The biological activity in vitro of the synthesized 1-desoxy-2MD ( 6) was evaluated and this analog was found to have an affinity for the vitamin D receptor (VDR) similar as its parent compound 2MD ( 5) while being much less active in the transcriptional assay. The results of the biological tests in vivo are also discussed.
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More From: The Journal of Steroid Biochemistry and Molecular Biology
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