Synthesis and evaluation of geometric analogs of 1α, 25-dihydroxyvitamin D2 as potential therapeutics. Issue 164 (November 2016)

• Record Type: Journal Article
• Authors: Bolla, Narasimha Rao; Corcoran, Aoife; Yasuda, Kaori; Chodyński, Michał; Krajewski, Krzysztof; Cmoch, Piotr; Marcinkowska, Ewa; Brown, Geoffrey; Sakaki, Toshiyuki; Kutner, Andrzej
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 164(2016)
• Page Start: 50
• Page End: 55
• Publication Date: 2016-11
• Subjects: Analogs of 1α, 25-dihydroxyvitamin D2 -- Modified Julia olefination -- NOE effects -- VDR binding affinity -- CYP24A1 metabolic stability; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2015.08.025
• Languages: English
• ISSNs: 0960-0760

Abstract

Graphical abstract: Highlights: Analogs of 1α, 25-dihydroxyvitamin D2 were synthesized by an improved strategy. New (24 Z ) geometric isomers, PRI-1916 and PRI-1917, were obtained and identified. The structures were determined by 1 H and 13 C NMR, using COSY, HSQC and HMBC. Binding affinities were determined by a fluorescence polarization competition assay. New analogs were much more resistant to CYP24A1 than 1α, 25-dihydroxyvitamin D2 . 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 (24 Z ) 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 1 H and 13 C 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 (24 Z ) methyl analog PRI-1906 was much higher than that of (24 E ) analog PRI-1906, while the affinity of (24 Z ) 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.