Dissection of the Roles of Adenine Ring Nitrogen (N-1) and Exocyclic Amino (N-6) Moieties in the Interaction of 2-5A with RNase L

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

“…The above interdependence of N-γ t and S-γ ϩ conformational equilibria in 1-8 is consistent with the previous correlations in 8-aza-7-deaza-2Ј-deoxyguanosine. 12 In 2Ј-fluorinated nucleoside derivatives, however, the larger drive towards N and the higher preference for γ t rotamers in 8a3d-araG (5) compared to 8a3d-FaraG (6) is in contradistinction to the correlations of N sugar puckering and the higher preference for γ ϩ rotamers in adenine nucleosides. 48 We have observed no sign of interaction between 5Ј-OH and H-bonding acceptors on the heterocycle in 1-8, which would potentially influence γ rotamer populations.…”

“…A simple molecular modeling has shown that [N9-C1Ј-C2Ј-O2Ј/F2Ј] fragments adopt gauche-minus and gaucheplus conformations in N-and S-type conformations of 8a3d-araG (5) and 8a3d-FaraG (6), respectively. It could therefore be expected that the gauche effects of [N9-C1Ј-C2Ј-O2Ј/ F2Ј] fragments do not preferentially stabilize either of the pseudorotamers in 8a3d-araG (5) and 8a3d-FaraG (6). The effect of 2Ј-substituents in 8a3d-araG ( 5) and 8a3d-FaraG (6) on the N S equilibrium can be estimated by the comparison of ∆HЊ values in the following pairs of nucleosides: (i) the comparison of 8a3d-dG (2) and 8a3d-araG (5) gives the estimate of ϩ7.0 kJ mol Ϫ1 for the effect of 2Ј-OH on the N S equilibrium in 8a3d-araG ( 5) and (ii) the comparison of 8a3d-dG (2) and 8a3d-FaraG (6) yields ϩ2.3 kJ mol Ϫ1 for the effect of 2Ј-F on the N S equilibrium in 8a3d-FaraG (6).…”

“…It could therefore be expected that the gauche effects of [N9-C1Ј-C2Ј-O2Ј/ F2Ј] fragments do not preferentially stabilize either of the pseudorotamers in 8a3d-araG (5) and 8a3d-FaraG (6). The effect of 2Ј-substituents in 8a3d-araG ( 5) and 8a3d-FaraG (6) on the N S equilibrium can be estimated by the comparison of ∆HЊ values in the following pairs of nucleosides: (i) the comparison of 8a3d-dG (2) and 8a3d-araG (5) gives the estimate of ϩ7.0 kJ mol Ϫ1 for the effect of 2Ј-OH on the N S equilibrium in 8a3d-araG ( 5) and (ii) the comparison of 8a3d-dG (2) and 8a3d-FaraG (6) yields ϩ2.3 kJ mol Ϫ1 for the effect of 2Ј-F on the N S equilibrium in 8a3d-FaraG (6). The smaller ∆∆HЊ drive towards N in 8a3d-FaraG ( 6) cannot be explained by the consideration of the gauche effect of [O-C-C-F] being stronger than that of the [O-C-C-O] fragment.…”

“…The anomeric effect of 8-aza-3-deazaguanine (≈19.5 kJ mol Ϫ1 ) is considerably stronger than the anomeric effect of adenine (14.7 kJ mol Ϫ1 ), 33 which has an important impact on the hybridisation state of C1Ј. The ratio of the sp 3 vs. sp 2 nature of C1Ј influences the gauche effects where C1Ј is the intervening atom as in [N9-C1Ј-C2Ј-O2Ј/F2Ј] fragments in 8a3d-araG (5) and 8a3d-FaraG (6). On the other hand, electronegative fluorine exerts an electron-withdrawing effect and back donation on the neighbouring atoms, thus changing their p character and deforming their bond lengths and bond angles.…”

“…1 Various ring and sugar modifications on 3-deazaguanosines have been made, 2-4 resulting in a wide modulation of the biological activity. Nucleobase modified nucleosides are, in addition, potentially important as probes in studies of mechanisms and catalytic activities of individual functional groups 5, 6 or as an aid in NMR assignments. An antisense oligonucleotide has to adopt an A-type conformation with characteristic N-type sugar puckering for higher affinity to the RNA target, which can be achieved by the nucleobase modifications that also influence pairing specificity.…”