title: Synthesis and evaluation of geometric analogs of 1α,25-dihydroxyvitamin D2as potential therapeutics.
abstract: 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 of1H and13C 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.
authors: Pharmaceutical Research Institute, 8 Rydygiera, 01-793 Warsaw, Poland. Electronic address: n.bolla@ifarm.eu.
authors: Narasimha Rao
authors: NR
authors: Bolla
authors: Faculty of Biotechnology, University of Wroclaw, 14a Joliot-Curie, 50-383 Wroclaw, Poland.
authors: Aoife
authors: A
authors: Corcoran
authors: Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama 939-0398, Japan.
authors: Kaori
authors: K
authors: Yasuda
authors: Pharmaceutical Research Institute, 8 Rydygiera, 01-793 Warsaw, Poland.
authors: Michał
authors: M
authors: Chodyński
authors: Pharmaceutical Research Institute, 8 Rydygiera, 01-793 Warsaw, Poland.
authors: Krzysztof
authors: K
authors: Krajewski
authors: Pharmaceutical Research Institute, 8 Rydygiera, 01-793 Warsaw, Poland.
authors: Piotr
authors: P
authors: Cmoch
authors: Faculty of Biotechnology, University of Wroclaw, 14a Joliot-Curie, 50-383 Wroclaw, Poland.
authors: Ewa
authors: E
authors: Marcinkowska
authors: School of Immunity and Infection, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, West Midlands B15 2TT, UK.
authors: Geoffrey
authors: G
authors: Brown
authors: Department of Biotechnology, Faculty of Engineering, Toyama Prefectural University, 5180 Kurokawa, Imizu, Toyama 939-0398, Japan.
authors: Toshiyuki
authors: T
authors: Sakaki
authors: Pharmaceutical Research Institute, 8 Rydygiera, 01-793 Warsaw, Poland.
authors: Andrzej
authors: A
authors: Kutner
mesh_terms: D001667:Binding, Competitive; D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D004872:Ergocalciferols / Q000138:chemical synthesis* / Q000737:chemistry*; D004926:Escherichia coli / Q000378:metabolism; D004952:Esters / Q000737:chemistry; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D020033:Protein Isoforms; D018167:Receptors, Calcitriol / Q000235:genetics; D011994:Recombinant Proteins / Q000737:chemistry; D013050:Spectrometry, Fluorescence; D016896:Treatment Outcome; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics / Q000378:metabolism
chemical_list: D004872:Ergocalciferols; D004952:Esters; D020033:Protein Isoforms; D018167:Receptors, Calcitriol; D011994:Recombinant Proteins; C579457:VDR protein, human; C003564:1,25-dihydroxyergocalciferol; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase
keywords: Analogs of 1α,25-dihydroxyvitamin D(2); CYP24A1 metabolic stability; Modified Julia olefination; NOE effects; VDR binding affinity