Stereochemical studies on nucleic acid analogues. I. Conformations of α‐nucleosides and α‐nucleotides: Interconversion of sugar puckers via O4′‐exo

Abstract

The preferred conformations of ribo and deoxyribo alpha-nucleosides and alpha-nucleotides, the stereoisomers of the naturally occurring beta-isomers, are worked out by minimizing the conformational energy as a function of all the major parameters including the sugar ring conformations along the pseudorotation path. The results of the studies bring out certain distinct conformational features that are at variance with their beta counterparts. The range of glycosyl conformations are found to be not only quite restricted here but favor predominantly the anti conformation. The syn glycosyl conformation for the entire region of P values are found to be energetically less favorable, with the barrier to anti in equilibrium with syn interconversion being higher especially in alpha-ribonucleosides. The energetically preferred range of pseudorotation phase angles (P) is also considerably restricted and P values corresponding to the C1'-exo range of sugars are highly unfavorable for alpha-nucleosides, in sharp contrast to the broad range of sugar ring conformations favored by beta-isomers. While both trans congruent to 180 degrees and skew congruent to 270 degrees conformations around the C3'-O3' (phi') bond are favored for alpha-3'-nucleotides with deoxyribose sugars, ribose sugars seem to favor only the skew values of phi'. Most interestingly and in sharp contrast to beta-stereoisomers, an energy barrier is encountered at P values corresponding to O4'-endo sugars. This suggests that the possible sugar pucker interconversion between C2'-endo/C3'-exo and C3'-endo/C2'-exo in alpha-anomers could take place only through the O4'-exo region. Likewise the possible path of anti in equilibrium with syn interconversion in alpha-nucleosides is not via high anti, in sharp contrast to beta-nucleosides. These observations should be borne in mind while assigning the sugar ring conformers in alpha-nucleosides and those containing them from nmr investigations. Comparison of the results with beta-anomers seem to suggest on the whole a lack of conformational variability or the restricted nature of alpha-stereoisomers. This could be one of the reasons for its nonselection in the naturally occurring nucleic acids.

In What Ways Do Synthetic Nucleotides and Natural Base Lesions Alter the Structural Stability of G-Quadruplex Nucleic Acids?

“…It was, therefore, suggested that PS-ODN interacts with the highly cationic V3 loop. α -Nucleosides, which cannot adopt syn glycosidic conformation [ 177 ], were substituted for Ts of the loops and dGs of tetrads of the native TBA GQ. Depending on the location of substitution, the GQ was either stabilized or destabilized by the α -Ts in the loops.…”

Anomeric DNA quadruplexes

“…Therefore, core modifications represent substantial interest from the structural point of view even regardless of their impact on TBA activity. Particularly, the inability of α nucleotides to adopt syn conformation 33 makes the design of modified GQs more predictable in terms of folding topology. Thus, artificial GQ structures may emerge useful tools in the design of new therapeutic GQ scaffolds.…”

“…34 Additionally, it should be taken into account that unlike natural β anomers, α nucleosides cannot adopt a syn conformation. 33 Therefore, two α-deoxyguanosine strands must be arranged in parallel. In this case one of two unimolecular topologies can be proposed for GQ structure formed by aptamer A12, i.e., TBAlike anti-parallel chair, or anti-parallel basket (Fig.…”

The α-D-anomer of 2′-deoxycytidine: crystal structure, nucleoside conformation and Hirshfeld surface analysis

“…The -2 0 -deoxyribofuranosyl moiety shows a preference for two principal sugar conformations, namely C3 0 -endo (N) and C2 0 -endo (S) (Altona & Sundaralingam, 1972;Sundaralingam, 1971). In contrast, studies on -2 0 -deoxy-and ribonucleosides showed that these anomers prefer mainly C3 0 -exo, C2 0 -exo and C4 0endo conformations (Latha & Yathindra, 1992;Sundaralingam, 1971). As can be seen in Fig.…”

“…The different conformational properties of the /-anomers were attributed to the differences in the steric interactions between the nucleobase and the sugar moiety (Sundaralingam, 1971;Latha & Yathindra, 1992). However, compared to the number of X-ray analyses of -nucleosides, studies on -nucleosides are extremely limited (Sundaralingam, 1971;Latha & Yathindra, 1992). Surprisingly, among the canonical -nucleosides, only the solid-state conformations of -cytidine (Post et al, 1977) and -2 0 -deoxythymidine (3) (Gö rbitz et al, 2005) have been reported.…”