Profile of ligand specificity of the vitamin D binding protein for 1α,25-dihydroxyvitamin d3 and its analogs

摘要: The profile of structural preference for the ligand binding domain human vitamin D protein (DBP) was determined by steroid competition assay 71 analogs 1 alpha,25-dihydroxyvitamin D3 [1 alpha,25(OH)2D3]. following categories modification were evaluated [values represent fold change; R = reduction, I increase in to DBP from reference alpha, 25(OH)2D3]: (1) deletion A ring alpha-hydroxyl-(20-1600I); (2) conversion triene system previtamin form (6-40R); (3) addition substituents carbon 11 C (4-14R); (4) inversion C/D junction (8-20R); (5) unsaturation (16-ene; 4-140R); (6) replacement hydrogen with deuterium atoms (no effect); alteration side chain (7) adding or deleting (5-12R); (8) fluorines (0.2-10R); (9) presence (22-ene, 0-5R; 23-ene, 3R-10I; 23-yne, 5-20R); (10) hydroxyls (2-100R); and (11) an aromatic (0-20I). Thus could tolerate only modest changes structure alpha,25(OH)2D3 without a reduction analog. increases seen triple bond at carbon-23 may be indicative preferred conformation flexible 25(OH)2D3 chain. In addition, comparison made that HL-60 cell nuclear receptor. Both domains equivalently accommodate side-chain cyclopropyl group, 22-ene lengthening two carbons, four six fluorine atoms, substitution oxygen 22, 22-[m-(dimethylhydroxymethyl)phenyl] group DPB better than receptor 22-(p-hydroxyphenyl) absence alpha-hydroxyl. contrast, modifications: 16-ene, 16-ene plus 23-yne unsaturation, beta-hydroxyl.