Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
5513220 | The Journal of Steroid Biochemistry and Molecular Biology | 2016 | 6 Pages |
â¢Analogs of 1α,25-dihydroxyvitamin D2 were synthesized by an improved strategy.â¢New (24Z) geometric isomers, PRI-1916 and PRI-1917, were obtained and identified.â¢The structures were determined by 1H and 13C NMR, using COSY, HSQC and HMBC.â¢Binding affinities were determined by a fluorescence polarization competition assay.â¢New analogs were much more resistant to CYP24A1 than 1α,25-dihydroxyvitamin D2.
An improved convergent strategy was developed for the synthesis of the previously obtained side-chain extended and rigidified analogs of 1α,25-dihydroxyvitamin D2, PRI-1906 and PRI-1907. New (24Z) geometric isomers of the analogs, PRI-1916 and PRI-1917, were also obtained and identified. These side-chain isomers were separable by flash chromatography, as C-25 alcohols, from the synthetic precursors of PRI-1906 and PRI-1907, respectively. The structures of new analogs were determined by advanced techniques of 1H and 13C NMR, including COSY, HSQC and HMBC sequences. Binding affinities of the geometric analogs PRI-1906 and PRI-1916 and their respective C-26, C-27 homologs PRI-1907 and PRI-1917 for the full-length human vitamin D receptor were determined by a fluorescence polarization competition assay. The binding affinity of (24Z) methyl analog PRI-1906 was much higher than that of (24E) analog PRI-1906, while the affinity of (24Z) ethyl analog PRI-1917 was lower than that of the respective PRI-1907. Investigation of the metabolism of these compounds by human CYP24A1 revealed they are much more resistant to CYP24A1 than 1α,25-dihydroxyvitamin D2, indicating they could have longer-term biological effects on target tissues.
Graphical abstractDownload high-res image (115KB)Download full-size image