Active Vitamin D Analogs with Restricted Conformation Mobility : Synthesis, Receptor Binding and Regulation of Gene Expression

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Conformational analysis of vitamin D indicated that the region in space where vitamin D side chain moves about can be grouped into four. We temed these regions as A,G,EA,and EG.We designed four conformationally restricted analogs side side chains are confined to occupy only one of these four spatial regions : (20R,22R) -22-methyl-1,25-dihydroxyvitamin D_3 (1), (20R,22S) -22-menthyl-1,25-dihydroxyvitamin D_3 (2), (20S,22R) -22-menthyl-1,25-dihydroxyvitamin D_3 (3), (20S,22S) -22-menthyl-1,25-dihydroxyvitamin D_3 (4). Each analog was synthesized stereoselectively via diastereoselective conjugate addition of organocuprate to steroidal 22-en-24-one as the key step. VDR affinities of these analogs were tested and found to increase in the order EG<G<A<EA in termas of the regions. The results indicate that the important spatial regions of vitamin D to bind to VDR are A and EA.Vitamin D analogs fluorinated at C (4) and C (19) were syntherized as probes for ^<19>F-NMR analysis of vitamin D-VDR complex. It is promising that using these analogs we can analyze the A-ring conformation of vitamin D when bind to VDR by ^<19>F NMR.VDR-ligand binding domain was successfully syntherized in ten mg scale by using recombinant DNA technique.