β-Cyanuryl Ribose, β-Barbituryl Ribose, and 6-Azauridine as Uridine Mimetics.

Abstract

Uridine (U) mimetics are sought after as tools for biochemical and pharmacological studies. Previously, we have identified recognition patterns of U by proteins. Here, we targeted the characterization of uridine mimetics—cyanuryl-ribose (CR), barbituryl-ribose (BR), and 6-azauridine (AU)—with a view to identify analogs with potentially more binding interactions than U with target biomolecules. We found that CR, BR, and AU retain selective U’s natural H-bonds with adenosine vs guanosine. CR/AU and BR were 100- and 10,000-fold more acidic, respectively, than U. Under physiological pH, 54, 51, and 77% of CR, AU, and BR molecules, respectively, are ionized vs 13% for U. The electron-rich nature of CR and BR vs U was reflected by their 13C NMR chemical shifts and ε values. CR/AU and BR prefer N conformation (up to 73%) vs U (56%). Unlike U that prefers gg conformation around exocyclic methylol (48%), CR/AU and BR prefer both gt and gg rotamers. In conclusion, replacement of uridine’s C6 by N or carbonyl, or C5–C6 by an amide, results in significant changes in U’s ionization, electron density, conformation, base-stacking, etc., leading to potentially tighter binding than U with a target protein or nucleic acid and potential use for various biochemical and pharmacological applications.