8-Aza-3-deazaguanine modification strengthens the anomeric effect and affects other conformational preferences of modified guanine nucleosides

Abstract

A variable temperature-dependent ¹H NMR conformational analysis of ³J_HH coupling constants and NOE enhancements of a series of 8-aza-3-deaza modified guanine nucleosides 2 and 4–8 has been performed in DMSO-d₆ and the results compared to those for natural nucleosides dG (1) and G (3). 8-Aza-3-deaza nucleobase modification leads to the stabilization of N-type conformers by ΔΔH° of 3.1 kJ mol⁻¹, which has been attributed to the strengthening of the O4′–C1′–N9 anomeric effect. The strengthening of the anomeric effect of 8-aza-3-deazaguanine compared to guanine is explained by the redistribution of electron density from N9 into the pyridine moiety which facilitates n_O4′ → σ*_C1′–N9 orbital interactions. The anomeric effect of 8-aza-3-deazaguanine in 8a3d-dG (2) is approximately 19.5 kJ mol⁻¹ with the assumption that the steric effects of nucleobases in dG (1) and 8a3d-dG (2) are comparable. 2′- and 3′-Substituents drive the N ⇌ S equilibrium via their involvement in gauche effects, which are only moderately affected by the nucleobase modification. The 2′-OH group in ribo (4), xylo (7) and 3′-deoxyribo (8) counterparts, however, drives the N ⇌ S equilibrium towards S by the gauche effect of the [N9–C1′–C2′–O2′] fragment, which has been strengthened by ΔΔH° of 1.8 kJ mol⁻¹ due to 8-aza-3-deaza nucleobase modification. 2′-F in the arabino analogue 8a3d-FaraG (6) showed conformational preferences which are nucleobase specific and could not be attributed to the gauche effects. The larger population of γ^t rotamers in 1–8 correlates with the larger population of N-type conformers.