Metal ion coordination to azole nucleosides

To evaluate the possibility of introducing azole nucleosides as building blocks for metal-mediated base pairs in artificial oligonucleotides, imidazole nucleoside, 1,2,4-triazole nucleoside and tetrazole nucleoside have been synthesized and characterized. The X-ray crystal structures of p-toluoyl-protected 1,2,4-triazole and tetrazole nucleosides are reported. Contrary to the situation primarily found for deoxyribonucleosides, the sugar moieties adopt C3'-endo conformations. The acidity of the P nucleosides increases with increasing number of nitrogen ring atoms, giving pK(a) values of 6.01 +/- 0.05, 1.32 +/- 0.05 and <-3, respectively. This decrease in basicity results in a decreasing ability to form 2:1 complexes with linearly coordinating metal ions such as Ag+ and Hg2+. In all cases,the Ag+ complexes are of higher stability than the corresponding Hg2+ complexes. Whereas imidazole nucleoside forms highly stable 2:1 complexes with both metal ions (estimated log 2 values of > 10), only Ag+ is able to reach this coordination pattern in the case of triazole nucleoside (log beta(2) = 4.3 +/- 0.1). Tetrazole nucleoside does not form 2:1 complexes at all under the experimental conditions used. These data suggest that imidazole nucleoside, and to a lesser extent 1,2,4-triazole nucleoside, are likely candidates for successful incorporation as ligands in oligonucleotides based on metal-mediated base pairs. DFT calculations further corroborate this idea, providing model complexes for such base pairs with glycosidic bond distances (10.8-11.0 angstrom) resembling those in idealized B-DNA (10.85 angstrom).