摘要:

IntroductionThe substitution of the ring oxygen atom with sulfur in nucleoside analogues has been extensively investigated as means to derive potential antiviral and antitumour drugs.1–3In addition to the structural changes caused by C–S bonds being longer than C–O bonds, the introduction of a sulfur atom has many other implications, like resistance toN-glycosidic bond hydrolysis by nucleoside phosphorylases,4and perturbation in the electronic environment of the heterocyclic ring due to the lower electronegativity of sulfur relative to oxygen. 4′-Thio-β-D-oligoribonucleotides are a promising class of antisense agents which exhibit improved stability toward nuclease degradation while retaining specific hybridisation with complementary RNA target sequences and favourable thermal stability.5–10The endocyclic oxygen-to-sulfur substitution also influences the ability of modified oligonucleotides to serve as substrates for enzymes by changing groove dimensions of the hybrid duplex.TheD-ribo orD-2′-deoxyribofuranose moieties in natural nucleosides are involved in a two-state conformational equilibrium between two distinctly identifiable North (N) and South (S) conformations which interconvert fast on the NMR time scale.11–13The two-state N⇌S pseudorotational equilibrium in solution is controlled by the competing anomeric andgaucheeffects.14The 2′-OH and 3′-OH groups drive the N⇌S equilibrium by a tendency to adopt agauchearrangement of O–C–C–O fragments with O4′–C1′/C4′ bonds.15The heterocyclic bases inN-nucleosides drive the two-state N⇌S pseudorotational equilibrium of the constituent β-D-pentofuranosyl moieties by two counteracting contributions from (i) the inherent steric effect of the nucleobase 16and (ii) the anomeric effect.17–19We have initiated a conformational study of a series of β-D-2′-deoxy-4′-thioribonucleosides1–4, their ribo counterparts5–8and α-D-4′-thioribonucleosides9and10in order to assess how the electronic changes caused by replacement of oxygen with sulfur change the stereoelectronic effects which govern their conformational degrees of freedom and possibly perturb the pKavalues. The conformational preferences of1–10in aqueous solutions were examined with the use of temperature- and pH-dependent1H NMR spectroscopy. Our previous study has shown that 4′-thiothymidine (4) and its 5-bromovinyl analogue adopt nearly equivalent N⇌S equilibria, as does natural nucleoside.20A quantitative evaluation of ΔH ° of pyrimidinevs.purine aglycon through a comparison of the respective ΔH ° values of the N⇌S pseudorotational equilibria of1–10has given us a broader insight into the energetic strength of the S4′–C1′–N9vs.O4′-C1′–N9 anomeric effects in 2′-deoxyribonucleosides. The replacement of O4′ with sulfur is, in addition, influencing the population of γ-rotamers and the driving of the N⇌S equilibrium by the 3′-OH group through the energetic preference along [S–C–C–O] fragments in1–10.

ISSN:1472-779X    

出版商:RSC    

年代:1999

数据来源: RSC